Field of Science

A novel paradigm in understanding antibiotic action?

We have gained a detailed understanding of antibiotic action over the last 30 years or so, or at least we think so. Almost all the major current antibiotics are thought to work through a handful of processes that disrupt or halt bacterial growth: cell wall growth inhibition, protein synthesis inhibition, metabolism inhibition and DNA synthesis inhibition.

But a paper published a couple of weeks ago in Cell demonstrates a novel and previously unthought of mode of action for antibiotics- free radical generation and subsequent bacterial cell death. The surprising thing is that the authors of the paper don't demonstrate this for a particular antibiotic. They think that all antibiotics may work the same way. If this is true, it will lead to a reevaluation of our understanding of all antibiotic action. In their hands, three of the best known antibiotics around that have very different modes of action- penicillin, norfloxacin and kanamycin- showed the generation of free radicals and subsequent bacterial death of growth inhibition.

They observed hydroxyl radical production after bacterial cells were treated with all three antibiotics. The radical formation was visualized through a fluorescein derivative that fluoresces after reacting with hydroxyl radicals (apparently it's not possible yet to directly test for radical formation in-vivo). To substantiate the radical phenomenon (pun intended), they added an iron chelator that chelates Fe(II) thus inhibiting the well-known Fenton reaction that produces hydroxyl radicals from the reaction of Fe(II) and hydrogen peroxide. After the iron chelator was added, bacterial survival increased, indicating that radicals were playing a role in inhibiting the survival. Similar behaviour was observed after addition of a hydroxyl radical quencher.

The authors think that all three classes of antibiotics act by inhibiting the electron transport chain and depleting NADH which is converted to NAD+ in the reducing potential generating set of reactions. This impairs the chain and generates superoxide that disrupts iron-sulfur clusters in the chain, generating Fe(II). The Fe(II) reacts with the H2O2 produced by the reaction of superoxide with superoxide dismutase, thus producing toxic hydroxyl radicals.

Whether this study will be unique or general remains to be seen. As with other such biological studies, it is fraught with complications, most importantly that of distinguishing between cause and consequence. What else happens when the iron chelator and radical quencher are added? Are the radicals the cause of bacterial death or simply a byproduct of some other process induced by the antibiotics?

In any case, this paper is very interesting and sounds like one of those ideas that may simply indicate an incidentally exciting observation, or a real sea-change in a well-established paradigm. It was judged significant enough though to be included in C & EN's end of year issue as a 2007 chemistry highlight of the year.

Another need for nuclear energy

This is what happens when there is inertia towards construction of reactors for peaceful purposes:
"Hospitals across North America have been forced to cancel tests for cancer and heart disease because the unexpected closure of a Canadian nuclear reactor has led to a sudden shortage of medical isotopes.

The 50-year-old National Research Universal (NRU) reactor located in Chalk River, Ontario, was shut down on 18 November for scheduled maintenance and was due back online by mid-December. But Atomic Energy Canada, which owns and operates the facility, extended the outage to install safety-related equipment, including upgrades to the reactor cooling pumps. The reactor supplies about 60% of the molybdenum isotopes used in medical applications globally, including molybdenum-99, which decays into technetium-99m and is used in about 16 million nuclear medicine procedures annually in the United States...The shortage has reignited a discussion over securing the US supply of medical isotopes by building a reactor in the United States."
Again, there's no sense if the debate about nuclear weapons and terrorist attacks is regularly conflated with peaceful and necessary uses of nuclear energy.

Semen gives us a Christmas gift

In what for me is one of the most novel papers I have read this year, researchers in the US, Spain and Germany have found that human semen has a protein that aids HIV in increasing its transmission and attachment to host cells in the female genital tract. This paper in Cell is fascinating and reveals a novel mode through which HIV acts to its advantage by latching on to a rare protein in semen. This protein can possibly increase the spread of infectious HIV through sex more than 100,000 times.

In a nutshell, the authors found a protein in human semen- prostatic acidic phosphatase (PAP)- which can kind of pick up infectious HIV particles and transmit them. This protein can increase the transmission of HIV several thousand fold. As an interesting and significant side-point, the rate of transmission of HIV through sex is actually pretty crummy and that is one of the reasons the AIDS epidemic is not as bad as it could have been (No, I am not advocating unsafe sex...unless your favourite game is Russian roulette)

But in an even more novel development, the authors find that PAP forms amyloid fibrils that constitutes the form in which HIV gets transmitted. HIV latches on to this amyloid form and then infects host cells much more efficiently. Interestingly, now about 30 disorders have been found in which amyloid has been involved. Nor is amyloid restricted to Alzheimer's Aß peptide. Many proteins can form the characteristic conformational signature of amyloid under the right conditions. Amyloid increasingly seems to be a timeless passenger whose fate has been possibly intertwined with ours for millennia.

I will leave it to you to read the paper and will probably have more detailed thoughts later. But the paper illustrates several points; firstly, how evolution again may have adapted HIV to take advantage of its natural environment. Semen is the lifeblood of HIV when it's sexually transmitted and any modification that allows the virus to thrive in semen and take advantage of the biomolecular machinery in semen will prove hugely important to it. Several other substances in semen also buttress HIV, a virus that is so fragile that exposure to the natural environment incapacitates it in seconds. Basic amines in semen like spermine for example can neutralise the dangerous acidic environment of the vagina. It is one of the grim ironies of nature that a life-form that is extraordinarily susceptible to the elements wreaks havoc in the human world on an unparalleled scale. The paper also illustrates a possible point of intervention in stopping the transmission of HIV, although much detail needs to be fleshed out before rational therapy can be contemplated.

But most importantly, the paper again indicates how fascinating science is, where novel insights keep on transforming both basic and applied science. Stem cells, a novel and hiterto unnoticed paradigm about how antibiotics work, and now this. Good year for the biomedical community and good year for Cell. And this paper is definitely one of the better Christmas gifts the medical world could have received.

Opinion

Amazing pumping

Ion pumps are the life force of living organisms. It's hard enough for anyone to publish a single ion pump crystal structure.

It's even harder for the same group to publish 3 ion pump structures in Nature.

Sodium-Potassium pump
Proton pump
Calcium pump

In the same issue of Nature.

This looks like a staggering amount of work. Amazing.

Editor's summary, News and Views

Time to take MRSA seriously

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The public is fascinated by exotic names. West Nile Virus. Ebola. Avian Flu. This is in spite of the fact that West Nile Virus killed 7 human beings in the US. For all the rhetoric about bioterrorism and anthrax and the siphoning off of much-needed funds into these ares by the administration, what finally kills us is what's in the backyard, not what's imported from abroad. What needs to be paid attention to is the much larger threat of antibiotic-resistant infectious diseases in this country. Before they consider threats from beyond borders, they need to consider threats within. The statistics are uncomfortable to say the least. Here's a very recent important JAMA report from October 2007: 18,000 deaths from MRSA. That's a stupendous number in this age of antibiotics if we think about it. It makes the number of MRSA victims more than the number of AIDS victims. Yes, more than the number of AIDS victims. That should put things in perspective.
"These data represent the first US nationwide estimates of the burden of invasive MRSA disease using population based, active case finding. Based on 8987 observed cases of MRSA and 1598 in-hospital deaths among patients with MRSA, we estimate that 94 360 invasive MRSA infections occurred in the United States in 2005; these infections were associated with death in 18 650 cases. The standardized incidence rate of invasiveMRSAfor calendar year 2005 was 31.8 per 100 000 persons. The incidence of other important invasive pathogens in 2005, such as invasive infections with S pneumoniae or Haemophilus influenzae, ranged from 14.0 per 100 000 to less than 1 per 100 000, largely due to the availability and success of vaccination."
For once, the Bushesque rhetoric "Be afraid" holds at least some water.

The impressive chemistry knowledge of talk-show hosts

I got this from Philip Ball's blog. Jeremy Paxman is a talk-show host in the UK. Apparently he has some quiz session where invariably a few science questions creep in. This is how the intrepid host tackles chemistry questions:
Paxman: “Which hydrated ferrous salt was once known as green vitriol?”
Student: “Iron sulphate.”
Paxman: “No, it’s just sulphate.”
Score one for the need to enroll talk-show hosts in science class, or maybe just a class in reasonableness.

You have my ears mate

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© BBC
Extraordinary desert creature , the long-eared jerboa, captured for the first time on tape. But what is a little unnerving is
"These amazing, remarkable creatures are on the verge of extinction and we know almost nothing about them," warned Dr Baillie.
I wonder how many other creatures we have already rendered extinct without knowing anything about them. I wonder when we will render extinct the species of frog whose skin holds the cure for AIDS. Then again, blame God. She rendered 99% of species extinct in the past.

Bacteria win

Hints of tuberculosis bacteria in 500,000 year old human skulls. Richard Dawkins needs to write a new book, "The Selfish Bacterium". It seems all of human evolution is geared towards propagating bacteria and viruses. I serve you, my flagellar master.

The price of scientific ignorance will be liberty itself

The Bush administration has reached new highs in suppressing sound science and manipulating scientific evidence about key national issues to suit its whims and to divert funding towards politically expedient projects. But even more disturbing is the lack of scientific thought and skepticism and complicity of a public which cannot evaluate the actions of the administration for itself and which lets the government spend its tax dollars wherever it wants to. Important issues will never get funded if the public is not well-informed. If this trend continues, the price the country may pay for scientific ignorance would not just be a poor standard of living and retarded technological growth, but liberty and freedom themselves...

Read the rest of my post on Desipundit...

The OpenEye SAMPL challenge

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Finally something exciting. Me and some colleagues are taking part in the SAMPL (Statistical Assessment of the Modeling of Proteins and Ligands) challenge issued by OpenEye Software for their upcoming annual March meeting in Santa Fe, NM. OpenEye is well known for their ligand-based similarity searching tools that have proven to be superior to many others for virtual screening. I am looking forward both to visiting the state- a dream I have had since I was a kid- and working on the challenge.

The challenge basically is to perform the kinds of procedures to find and rank actives that are now a standard part of modeling in the pharmaceutical industry and elsewhere. The company will hand out three sets of data with small differences between them. Every set will have a couple of thousand ligands, with actives and lots of decoys mixed in with them. Sometimes a protein structure for the ligands might be thrown in. The goals are well-established and standard:

1. Virtual screening: find the actives, identify the decoys.
2. Crystallographic pose determination: find the correct crystallographic conformation for a few ligands in the active site
3. Estimating binding affinity: the hardest task, probably the holy grail of the industry. What more could we want if we could correctly rank order compounds beforehand in a project and estimate their binding affinity?

Literature searching is discouraged. The honor system is in effect. You can use whatever tools you can access. Participants in the challenge include many well-known academic groups as well as people from both Big Pharma and "Small" Pharma. Depending on the data set, we can choose all three or a subset of the above protocols as a challenge. Once we finish one set, we submit the results before a deadline and the next set will be released to us. The goal is not to win: in fact it's a win-win situation because we will always end up learning something interesting. Valuable lessons inevitably learned will include ligand preparation, docking, solvation energy estimation, and other aspects of both ligand-based and structure-based design. In this case, the goal is to see and analyze how people throughout the country can tackle some standard issues in early-stage drug discovery.

This should be fruitful and fun.

How many of you folks are sniffing toluene right now?

First it was benzene which was declared carcinogenic and toluene was supposed to replace it. Now studies indicate that toluene gives us a high. What next?
"Toluene is found in paint thinners, varnishes and even nail polish remover. Researchers from the University of Arizona and the National Institute of Drug Abuse (NIDA) demonstrate that toluene directly stimulates dopamine neurons causing dopamine release. Dopamine is a neurotransmitter and is released by reward centers in the brain causing a feeling of euphoria. The results suggest that the brain likely also interprets sniffing toluene as rewarding which can result in further abuse and possibly future use of other drugs.

Besides showing where in the brain toluene acts, the researchers also demonstrate that, surprisingly, toluene substances are most effective when used at low concentrations. Since toluene is rapidly absorbed in the brain, this might explain why the preferred mode of delivery is by "huffing" or "sniffing". Sniffing is frequently considered a harmless recreational or party drug but unlike other drugs, even a single session of inhaling the compound can disrupt heart rhythms
enough to cause cardiac arrest and lower oxygen levels enough to cause suffocation".

Two pioneers pass into history

Leslie Orgel (Nature obit), pioneer of ligand field theory and origin of life studies, and Arthur Kornberg (Mol. Cell obit), who "never met a dull enzyme". Kornberg must have felt satisfied, now that his son also won the Nobel Prize.

Enzymes as drug targets

"Enzymes catalyze multistep chemical reactions and achieve phenomenal rate accelerations by matching protein and substrate chemical groups in the transition state. Inhibitors that take advantage of these chemical interactions are among the most potent and effective drugs known. Recently, three new enzyme targets have been validated by FDA approval of new enzyme inhibitor drugs. These include mitogen-activated protein kinase, renin, and dipeptidyl peptidase IV. The drugs against these enzymes engage important enzyme functional groups, such as the active site serine in dipeptidyl peptidase IV."
There are more of them out there than we might imagine, and irreversible inhibitors are not always that bad.
"Some evidence now indicates that irreversible receptor protein-tyrosine kinase inhibitors might have advantages over reversible inhibitors in circumventing acquired resistance. The receptor protein-tyrosine kinases undergo ligand binding, homo-dimerization, hetero-dimerization, and internalization, whereas the intracellular nonspecific protein-tyrosine kinases lack these physiological processing events. Investigators speculate that reversible inhibitors may dissociate during receptor dimerization and internalization, and that significant signal trafficking can occur during the internalization.

By contrast, irreversibly inhibited receptor protein-tyrosine kinases would maintain inhibition throughout receptor recycling. Mutations that enhance receptor internalization would generate resistance to reversible inhibitors, but not to irreversible inhibitors. This is an interesting concept that remains to be explored.

Octagenarian worms on Prozac

"One goal of ageing research is to find drugs that would increase lifespan and vitality when given to an adult animal. To this end, we tested 88,000 chemicals for the ability to extend the lifespan of adult Caenorhabditis elegans nematodes. Here we report that a drug used as an antidepressant in humans increases C. elegans lifespan. In humans, this drug blocks neural signalling by the neurotransmitter serotonin. In C. elegans, the effect of the drug on lifespan is reduced or eradicated by mutations that affect serotonin synthesis, serotonin re-uptake at synapses, or either of two G-protein-coupled receptors: one that recognizes serotonin and the other that detects another neurotransmitterm octopamine. In vitro studies show that the drug acts as an antagonist at both receptors. Testing of the drug on dietary-restricted animals or animals with mutations that affect lifespan indicates that its effect on lifespan involves mechanisms associated with lifespan extension by dietary restriction. These studies indicate that lifespan can be extended by blocking certain types of neurotransmission implicated in food sensing in the adult animal, possibly leading to a state of perceived, although not real, starvation."
Nobel laureate Linda Buck's group finds out the ecstatic effects of human antidepressants on increasing worm lifespan. I am familiar with this "perceived state of starvation". I projected it during a Thanksgiving feast on Thursday leading to much generosity on the part of my hosts. Recall that caloric restriction is also possibly caused by wine molecule resveratrol.

Never a dull pharmacophore

The word "pharmacophore" was coined by Paul Ehrlich (a great word coiner; he also coined "magic bullet") as a reference to the essential chemical functionalities in a drug that makes it active. In the time since then, that word has been modified to mean the essential set of features in a drug, including their geometry and 3D orientation, that makes the drug active.

Pharmacophore modeling has become a stable of drug discovery and virtual screening, especially in the context of Computer Aided Drug Design (CADD). But even the average medicinal chemist is always interested in pharmacophores because he wants to know what's common between diverse structures that bind to a receptor that makes them active. Thus arises the goal of finding the "common pharmacophore" for different structures that bind to a site.

Sadly, the methods used for achieving this goal often fail because of some fundamental mistaken assumptions. The first assumption is that there is one, single pharmacophore. But ask anyone who uses a decent pharmacophore modeling program, and he or she will tell you that the program generates many pharmacophores, and it is not easy to decide which one among them is the "correct" one. The usual flaw in trying to come up with a common pharmacophore is to overlap compounds and look at common functionalities (hydrophobic, aromatic, charged etc.) in the same places. While this is a justifiable technique, the simple fact as noted above is that there are many ways to do this. One may overlay compounds so that say aromatic portions match with aromatic portions. But what about the other portions? How do we know that they don't constitute good binding features? Sometimes such trends or the lack thereof can be gleaned through traditional med chem and SAR, but more often than not they don't work.

In pharmacophore based virtual screening (VS), the technique is to come up with a pharmacophore and then compare it to a 3D library of possibly hundreds of thousands of compounds to find a lead that matches the pharmacophore in its 3D conformation. Since the pharmacophore essentially includes 3D information, the compounds in the databases have many conformers. In most cases, conformational searching for these compounds cannot be very exhaustive, but in most cases drug-like compounds have few rotatable bonds and so exhaustive conformation generation is not required.

Such simplistic techniques are seen in some early pharmacophore models. Say you have a peptide with a positive and negative end (NH2 and COOH) and you want to develop a good small molecule analog. You look at the minimum energy conformation of that peptide, or even the bioactive conformation if you know it. Then you note that the distance between the positive amino and negative carboxylate ends is 10 A. So with this pharmacophore, just an amino-carboxylate distance of 10 A, what you do is simply run this feature against a large 3D database of molecules hoping that you will come up with something that will also have the same distance between such two groups and therefore be active. This is admittedly the most simplistic pharmacophore ever, but Merck made it work for some fibrinogen agonists in 1992, which was an early example of pharmacophore-based virtual screening. The problem inherent in this protocol is that you are obviously neglecting other parts of the molecules which will dictate binding. Binding is a multipronged phenomenon and does not always depend on just two or three strong interactions.

This problem with investigating pharmacophores points to a larger truth; that ligands which bind to a common site in a protein may not bind the same way in many cases. For example, several people tried to come up with a "common pharmacophore" hypothesis for compounds binding to tubulin, such as taxol, epothilone and discodermolide. But a 2004 paper indicated that the binding site was promiscuous, that each ligand exploited the site in a unique way, and so trying to overlap them and come up with a common pharmacophore hypothesis was largely a futile effort.

If you have ever built a pharmacophore, you will also realise that it depends crucially on user input. Chemical intuition and knowledge of binding as well as known SAR data is very important for making decisions along the way. Pharmacophore modeling even more than other CADD protocols is not a black box.

In the future, pharmacophore models will continue to be used. Again, we must be realistic about their utility, which is seldom to come up with an ultra-potent lead, but to help in lead discovery. Some people think that because of this multiple-solution scenario, pharmacophore development is inherently flawed. I am more optimistic because first of all it is now possible to generate many pharmacophores and assess them against multiconformer libraries of a million compounds if necessary in a relatively short period of time. Secondly, model generation combined with careful analysis and astute chemical intuition has been known to pay dividends in the past, and there is no reason why it should not pay dividends in the future. At some point in the future, I am planning a post on some more details of pharmacophore modeling.

Of interest: A pharmacophore for kinase frequent hitters

Man-sized scorpion's claw found

It is morbidly wondrous to imagine such creatures paddling the oceans and swarming the earth in the past. No time machine for me...brrr.

Skin cells to stem cells

"As news of the success by two research teams spread by e-mail, scientists seemed almost giddy at the likelihood that their field, which for its entire life has been at the center of so much debate, may suddenly become like other areas of biomedical science: appreciated, eligible for federal funding and wide open for new waves of discovery."
Wow. I have said this many times before; no matter how much egghead Presidents and religious bigots suppress scientific research, science moves on. It may trudge or even falter sometime, but it will progress. Of that one thing we can be sure.

Now, researchers have come up with a method to use 4 genes to induce skin cells to transform into stem cells through a retroviral vector. I am yet to read the two reports in Science and Cell in detail (here and here) but the news for now sounds like a real breakthroughs; even the White House dispensed their insipid bleatings about it. But to hell with them for now. I always knew there could be a way around this, and now here it seems to be. Made the front page of the New York Times. More details later.

Links via email from Patrix

Mountains of malicious mutations

"Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy."
The future, ladies and gentlemen (or at least a small part of it). Commentary here.

Ethanol: saviour of the unfortunate...and the stupid

Ethanol, the much reviled yet irresistible satanic temptation that has plagued the human world for centuries, can actually be a giver of life in some situations...

Read the rest of the entry on Desipundit...

Increasing the bioavailability of Curcumin

"To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin"
The article is by Bharat Aggarwal, who first demonstrated that curcumin inhibits NfkB. The strategy can likely be used for other compounds too.

Give the kid S-15535, said Dad

"The researchers also found that they could alter the aggressive behaviour of their rats by manipulating the serotonin system. They gave the rats S-15535, a compound that binds exclusively to a neuron 'autoreceptor' that acts to dampen the serotonin system. This autoreceptor is called 5-HT1a. Binding to it seems to bring serotonin levels in the rats back to normal.

When even very low doses of S-15535 were used to bind to the receptors, de Boer found that both the serotonin and the violence of the pathologically aggressive rats returned to normal levels. The much more limited violence of naturally low-aggression rats could also be brought back to normal by the compound — but only by using higher doses. The compound seems to work by ‘fixing’ the serotonin breaking system, which becomes dysfunctional in the super-aggressive rats, says de Boer.
Hmm...drugs calming down violent rats...now who is going to convince Ann Coulter to enroll in the trial?

A simple substitution to possibly avoid phenol elimination

Several discussions on KP and other sites have focused on the unfeasibility of phenols as drugs because of their tendency to get glucuronidated, become more polar and get rapidly eliminated through the kidneys. So it seems helpful to know what one can do to a phenol in order to retain its electronic properties/steric properties but to prevent glucuronidation and elimination.

Just by chance I came across the following simple substitution: a phenol--->indole change, where the NH of the indole functions like the phenolic OH in hydrogen bonding situations but avoids the unfavourable glucuronidation. Certainly not a general solution, but a useful one that may work in some cases

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Reference:
5-, 6-, 7- and 8-amino-2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalenes: centrally acting DA and 5-HT1A agonists
European Journal of Medicinal Chemistry, Volume 28, Issue 9, 1993, Pages 693-701
P Stjernlöf, T Elebring, B Andersson, A Svensson, K Svensson, A Ekman, A Carlsson and H Wikström

Paraquat, paraquat...

We had a Fraser Stoddart protege over for a talk today, and I have to say I can now really understand the appeal of Sir Fraser's chemistry. The molecules are really pretty and simple, the synthesis is really simple, the physical methods used are elegant and simple, the effects are simple to understand...everything just looks so simple! The appeal clearly lies in the simplicity and the potential applications. Science should be fun, but slogging through a 50 step total synthesis can tend to at least temporarily sap the fun out of it. In this kind of science, it seems the fun is much easier to retain. No wonder it's creating a buzz.

Why I have scant patience with postmodernists

This echoes my sentiments perfectly:
"There are lots of things I don't understand -- say, the latest debates over whether neutrinos have mass or the way that Fermat's last theorem was (apparently) proven recently. But from 50 years in this game, I have learned two things: (1) I can ask friends who work in these areas to explain it to me at a level that I can understand, and they can do so, without particular difficulty; (2) if I'm interested, I can proceed to learn more so that I will come to understand it. Now Derrida, Lacan, Lyotard, Kristeva, etc. --- even Foucault, whom I knew and liked, and who was somewhat different from the rest --- write things that I also don't understand, but (1) and (2) don't hold: no one who says they do understand can explain it to me and I haven't a clue as to how to proceed to overcome my failures. That leaves one of two possibilities: (a) some new advance in intellectual life has been made, perhaps some sudden genetic mutation, which has created a form of "theory" that is beyond quantum theory, topology, etc., in depth and profundity; or (b) ... I won't spell it out."- Noam Chomsky
Postmodernists positively irk me (like they did a few days ago) when they contend that science is "just another way of knowing the world" and that other ways of "knowing" the world have equal validity. For them scientific truth holds no overwhelming importance, because it is as much a product of culture as anything else.

Fine, I say. Next time you get a bacterial infection, don't take antibiotics because they constitute just one particular approach of looking at the world advocated by one particular school of thought. After all, the fact that antibiotics kill bacteria does not constitute "truth", right? Instead, just pray, or visit shamans, or rub lotion all over your body.

See you later if you stay alive.

GHB in Aqua Dots

So there it is...they are ominously out to poison everybody, especially through a sinister delayed action transformation of a precursor into a deadly chemical. I could not be more thankful that I did not play with Aqua Dots as a kid...

In any case, does anyone know what it was in the dots that transformed into GHB (Dr. Sanjay Gupta probably does not)? Wikipedia lists two possible prodrugs, the lactone which is ring opened and 1,4 butanediol which is oxidised to GHB by alcohol dehydrogenase. Or maybe it's just proprietary ("Better killing through proprietary means")

You've lost that gut feeling

I came across a nifty Pfizer review published in JMC a couple of years ago about property-based optimization of drug candidates. There are many words of wisdom in it about various pharmacokinetic parameters and processes and related property optimization. One of the most interesting analyses I found was of gut absorption. Apparently:

1. Gut absorption is of two types; passive diffusion through lipid bilayers and passage through tight gap junctions. For drugs that undertake the latter route, size is obviously important. It turns out that dog GI gap junction pores are larger than in humans, so that a drug that passes readily through dogs won't pass readily through humans, highlighting the drawbacks of using dog models for studying human absorption. Also, Caco-2 cells seems to be bad models for drugs that undergo passage through this route. Fortunately, most drugs seem to pass via the first route, that is diffusion through lipid bilayers.

2. P-glycoprotein (PGP) and CYP3A4 (cytochrome P450 isozyme) are important in the gut, even if CYP3A4 expression is not as much as in the liver. The most interesting fact I read was that in case of PGP, the expression increases from top to bottom in the human digestive tract, with the least in the duodenum and the most in the colon. But for CYP the trend is opposite. Clearly this will influence structural considerations based on where the drug is going to be absorbed as well as drug delivery tactics.

3. CYP and PGP often work in concert in the gut, with PGP recycling substrates and offering them multiple times to CYP.

SAR for PGP and CYP definitely seems to be scarce, not surprisingly given that their substrate scope is quite large. Certain molecules such as the well-known immunosuppresants (eg. cyclosporin) have been identified to be rapidly metabolised by these enzymes. On the other hand, hyperforin from St. John's Wort can induce CYP expression and women on birth control pills might suddenly get a nasty surprise and find themselves pregnant; the hyperforin causes excessive metabolism of birth control molecules and reduces their blood levels to non-efficacious doses. Lipophilic drugs with electron rich groups can be choice fodder for CYP. Given the recent review highlighted by KinasePro which concluded that reducing lipophilicty should be a goal for avoiding poor absorption and promiscuous binding, this seems to be another good reason for losing the grease.

What doth a methylene?

One common strategy used by medicinal chemists for enhancing potency is to add a methylene carbon in a ring that's fitting into a lipophilic pocket. A methylene group usually contributes about 4 kJ/mol of affinity....or maybe not.

Gerhard Klebe's group at Marburg are studying inhibitors of thrombin in which they replace a cyclopentyl group by a cyclohexyl group. To their surprise they observe (DOI: 10.1002/anie.200701169) no change in binding affinity. Crystallography indicates no electron density for the part occupied by the cyclohexyl group but robust density for the cyclopentyl. The authors conclude that while the cyclohexyl binding is enthalpically unfavourable, entropically the six-membered ring can flip and twist and dance, which is favourable, and also does not provide much crystal density because of its flexibility. So unfavourable enthalpy is balanced by favourable entropy. MD simulations support this contention.
"What lesson can be learned from this example? Usually ligands are optimized in congeneric series. The addition of functional groups is expected to enhance binding; for example, the change from a five- to a six-membered ring should augment binding affinity by approximately 3–4 kJ/mol. However, even very similar ligands can exhibit very different binding properties that destroy a simple structure–activity relationship"
Also, the gain in binding affinity from a methylene depends on the system. Model systems based on octanol-water partitioning offer a value of about 0.7 kcal/mol. But of course octanol unlike a protein does not have a problem reorienting itself around the substrate. Thus, the value can be less for a protein. On the other hand, in cases where an extra methylene or methyl just about fills the remaining space in a pocket and packs tightly can provide 5 times as much binding affinity. This is true for example in case of tRNA synthatases (I got this from Alan Fersht's excellent book) As usual, exceptions abound to the generalisations, and Klebe's study provides another interesting example.

The Traffic Light

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Part of the reason I made the trip to London in September was a single goal; to stand at a particular traffic light near the British Museum and take a photo of myself standing there. Later when I told people about the reason, most thought it was silly, and perhaps it was. But all of us have a romanticised impression of certain people, places and events in our mind which other people could find silly. In this particular case, the person, place and event involved were profound even if little known to the general public. In fact this light was so important for me that I had made up my mind to visit London once in my lifetime for the sole purpose of standing at the light, if not for anything else. What was so special about this traffic light?

It was 1933. Adolf Hitler had come to power in January, The Depression was raging and the future looked bleak to many. On the morning of September 12, 1933, on a miserable, wet, quintessentially English autumn day, at the intersection where Russell Square meets Southampton Row, Leó Szilárd waited irritably at a traffic light waiting for it to change from red to green. He had just attended a lecture by the great English physicist Ernest Rutherford. Rutherford, known to many as the father of nuclear physics, was discussing the newly prophesied release of energy from atoms, most notably by science-fiction pioneer H G Wells in his book The World Set Free. In his baritone voice, Rutherford, acknowledged master of the atomic domain, dismissed this fanciful idea as nonsense. Any thought of releasing the energy locked in atoms, he said, was "moonshine".

Szilárd was irritated by this flippant repudiation. Accomplished as he was, how could even the great Lord Rutherford know what the future held in store? Szilárd, peripatetic Hungarian genius, imperious habitué of hotel lobbies, soothsayer without peer among scientists, had himself thought deeply about nuclear matters before, most often during his extended morning bathtub ablutions. Now waiting for the light to change, Szilárd pondered Rutherford's words...I will let the acclaimed nuclear historian Richard Rhodes do the talking here. It was the riveting description of this event in Rhodes's magnificent book that engraved it in my mind like nothing else:
"In London, where Southampton Row passes Russell Square, across from the British Museum in Bloomsbury, Leo Szilard waited irritably one gray Depression morning for the stoplight to change. A trace of rain had fallen during the night; Tuesday, September 12, 1933, dawned cool, humid and dull. Drizzling rain would begin again in early afternoon. When Szilard told the story later he never mentioned his destination that morning. He may have had none; he often walked to think. In any case another destination intervened. The stoplight changed to green. Szilard stepped off the curb. As he crossed the street time cracked open before him and he saw a way to the future, death into the world and all our woes, the shape of things to come"
Time cracked open indeed. What Szilard realised as he stepped off that curb, was that if we found an element that when bombarded by one neutron would release two neutrons, it could lead to a chain reaction that could possibly release vast amounts of energy. Leo Szilárd had discovered the nuclear chain reaction long before anyone else, six years before the discovery of nuclear fission and any inkling that anyone could have had about the release of atomic energy, let alone the woeful apocalyptic future that would await the world because of its release.

I first read Rhodes's book in 2000. The book begins with this story. The description is so riveting, the tale so profound and evocative, the person so singular and the implications so prophetic, that I resolved to visit Szilárd's traffic light, my traffic light, even if I had to once make a trip to London for just that. Since then, the event has been etched in my mind like words in red hot steel. Seven years later I got a chance.

The traffic light itself is completely non-descript, standing among dozens of other non-descript lights. We almost missed it; as I mused aloud about my great disappointment to my friend in a cafe and wished I had a map, a Spanish tourist sitting at the next table saved my life and procured one. The intersection was there. We had missed it by a block. Back we went and indeed there it was, with not an indication that a famous and prophetic physicist had seen into the future at that light some 75 years ago.

As it turned out at the time, Szilárd's choice for the element he was thinking about turned out to be wrong. Nuclear fission would be discovered only six years later in Germany after a series of close misses in Italy and France. But Leo Szilárd went down in history as the man who saw death before anyone else, a glimpse into mankind's Faustian pact with fate, the shape of things to come.

Ironically, when the first atomic bomb test was conducted in the New Mexico desert in the deathly stillness of the morning, in the midst of war and hope, the flash was so bright that it would have been seen reflected off the moon. It was, literally, "moonshine". The rest was history.

But I lived one of my dreams that day at that traffic light in London. Szilárd's traffic light. My traffic light.

Nuclear terrorism's unheeded assumptions?

Nuclear terrorism forms an important part of the armamentarium of one of the Bush administration's favourite pastimes- threat inflation. While it is true that the potential damage that terrorists could cause with even a 1 kT nuclear weapon is tremendous (Times Square NYC, noon on a weekday), there are many very realistic obstacles they need to overcome before they can acquire, process, build, transport and use any kind of a nuclear weapon.

The more realistic fear that governments and the public have is about dirty bombs, explosives packaged together with low-tech dispersive radioactive material that would largely circumvent the need to achieve the myriad steps needed to be in charge of a bonafide atomic device.

Writing in the Bulletin of the Atomic Scientists, Sonia Ben Ouagrham-Gormley challenges two assumptions made by proponents of a nuclear terrorist attack scenario: access to knowledge and the existence of a nuclear black market (exemplified by black market czar Pakistani scientist A. Q. Khan). Gormley correctly tackles the myth of easy access to nuclear material and knowledge and identifies the slip between the cup and the lip- from knowledge to working product.

She also questions the ease of facilitation of trade in the nuclear black market and doubts the existence of a dedicated clientele, an essential feature of any black market. The clientele should also have the understanding and sophistication to purchase and process nuclear material (In the early days of Al Qaeda, Bin Laden was had when someone sold him mercuric oxide as yellowcake).

Lastly, she questions the nature of materials that have been implicated in nuclear smuggling until now, most of which included depleted uranium and isotopes like Osmium 167, too ineffectual in a dirty bomb, let alone a weapon.

But I think she is missing out on three other important isotopes which are widespread products of research reactors, large scale reactors as well as medical research reactors- Iodine 131, Cesium 137 and Strontium 90. Out of these, Iodine 131 can be absorbed by the thyroid gland and leads to thyroid cancer, but its effects can be thwarted rather easily by ingesting tablets made of normal non-radioactive iodine, provided such tablets are easily available (the slow dissemination of these tablets was partly responsible for the large number of deaths from Chernobyl). Cs 137 and Sr 90 pose more serious problems, and I would think that more than anything else they would be choice materials for a dirty bomb. Both isotopes seem to strike the golden mean for radioactive lethality, possessing half-lives of 30 years and 28 years respectively; long enough to compare to a human life span, and short enough to be intensely radioactive. Moreoever, both elements chemically resemble two key elements in the human body. Cs 137 behaves somewhat like potassium and distributes throughout body fluids and compartments, whereas Sr 90 resembles calcium and deposits in bones, greatly increasing the risk of bone cancer. Both elements if ingested in reasonable amounts will pose almost irreparable risk and cause permanent damage.

I certainly don't think one should be immediately paranoid about these isotopes, but it is clear that if they wanted to, terrorists could steal them from multiple sources. I would think that any perceived scenario involving terrorists and dirty bombs should include discussion of these three isotopes, which because of their ease of access and purity are in some ways much more lethal than uranium or plutonium.

A chat with Nobel laureate Peter Agre

It’s not everyday that you get to have a relaxed, inspirational and informal almost one-on-one chat for an hour with a Nobel Prize winner. Yet that was what it was today morning...

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Unclear? No, it's nuclear

Nuclear energy promises to be the safest, most efficient and reliable source of energy in the fight against carbon-emissions and climate change. Yet there is deep-rooted opposition to it in the minds of the public and policy makers, mainly based on a dissonance between beliefs and reality. It is important for the public to transcend gut reactions, political pandering and partisanship and have balanced and sound knowledge of this very important energy source...

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The only existing O-H...F-C bond...not

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This is a beautiful piece of data re-interpretation. A few years ago, there was a report published about a compound which supposedly demonstrated the only instance of a solution O-H...F-C hydrogen bond. This seemed to provide some support for hydrogen bonding involving fluorine.

Now a Spanish group has published a nice paper in CC that provides a refutation and re-interpretation of the data that along with some calculations, indicates that the observed data is not due to a C-F...H-O hydrogen bond, but simply due to steric hindrance that makes the three fluorines of a CF3 group non-equivalent. In the former interpretation, it was assumed that the non-equivalence of two Fs of this group with the third F indicated that the third F was involved in hydrogen bonding. The new interpretation says that it is steric hindrance that prevents rapid rotation of the CF3 group, and makes the three Fs non-equivalent. Calculations support the interpretation.

Thus, now we will have to look for other instances in which there is bonafide C-F...H-O bonding. Quite a neat piece of careful data analysis supported by crystallography and quantum chemical caclulations.

Another fact mentioned in the paper reminds me of one of the more memorable papers that I have read; Stanford's Eric Kool's demonstration that difluorotoluene- an isostere of thymine in which Ns are replaced by Cs and Os are replaced by Fs- behaves like thymine when DNA polymerase inserts it opposite adenine.

Reference:
Is there any bona fide example of O–HF–C bond in solution? The cases of HOC(CF3)2(4-X-2,6-C6H2(CF3)2) (X = Si(i-Pr)3, CF3)
Chem. Commun., 2007, 4384 - 4386, DOI: 10.1039/b710304b

Please don't kill the message

It is very important not to let James Watson's statements stifle or intimidate scientists who are engaged in investigating all kinds of differences between various races. They need our protection and support now more than ever...

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Who is the fairer one; H or X?

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There's a fair amount of discussion going on at Kinasepro and TotMed regarding halogen bonding, a pretty interesting topic. I have read a few reports about it, but questions still linger. One of the questions raised by a commenter at KP was "How can a X-bond (halogen bond) be as strong as a H-bond?".

With good timing, there is a paper just published in JACS that seeks to investigate that kind of issue. It deals with competition between X and H bonding. The authors considered the four relatively simple molecules shown above that are studded with strong H-bond acceptors (pyridinyl and imidazolyl N), weak H-bond donor (imine C-H) and weak and halogens as X-bond acceptors and donors. Three of the molecules were the same except for different halogens.

The authors obtained several crystal structures, of the molecules themselves, as well as their complexes with the other molecules. The results indicate that a strong-strong H-bond donor-acceptor interaction (imadazole/pyridine N...OH hydrogen) trumps any X-bonding interaction, which is probably not too surprising. Weak X...X and N...X interactions such as Br...Br and N...Br are also trumped by weak-strong H-bonding interaction (imine C-H...pyridine N). However, N...I interactions do seem to be able to trump imine C-H...pyridine N interactions, although not strong-strong H-bonds.

Does this prove the general case of most X...X or X...N bonds being weaker than H-bonds? Yes, but not in the context of a crystal really, because crystallization is a hideously complex phenomenon to predict since it involves many subtle interactions and the sum of their costs and benefits. In a crystal or a protein for that matter, a H-bond could very well be sacrificed for a X-bond, not because the X-bond is per se stronger than the H-bond, but because the other parts of the molecule could interact in a way that is more favourable in the orientation with the X-bond rather than the H-bond.

It would also have been nice if they had mixed together the different halogen containing molecules. And I am still waiting for a good theoretical chemist to explain how the interaction can be worth 4-5 kcal/mol.

Reference:
Structural Competition between Hydrogen Bonds and Halogen Bonds
Christer B. Aakeröy,* Meg Fasulo, Nate Schultheiss, John Desper, and Curtis Moore
J. Am. Chem. Soc., ASAP Article 10.1021/ja073201c

Don't squelch eccentricity

Distinguished scientists including Edward O. Wilson (who for the record despised Watson before) and Richard Dawkins are now coming to James Watson's support. I suspect that the gut reaction that surfaced right after he made his statements obscured any kind of objective reasoning and patient analysis, as often happens with such socially explosive issues. Nobody can say that he had every justification for saying what he did, but more are now rallying to his side and denouncing his dismissal from Cold Spring Harbor and the cancellation of his lecture at the Science Museum. I have already stated my opinion in the last post; while the lecture cancellation was probably more aimed by the Science Museum at avoiding bad press, his dismissal from Cold Spring was unwarranted. One interesting point of view says that he in fact should have been allowed to appear at the Museum and quizzed in detail about his statements.
Robin McKie in the Guardian reports:
"In the end, Watson decided to return home, so no meetings occurred, a move that has dismayed many scientists who believed that it was vital Watson confront his critics and his public. 'What is ethically wrong is the hounding, by what can only be described as an illiberal and intolerant "thought police", of one of the most distinguished scientists of our time, out of the Science Museum, and maybe out of the laboratory that he has devoted much of his life to, building up a world-class reputation,' said Richard Dawkins, who been due to conduct a public interview with Watson this week in Oxford.

Nor is it at all clear that Watson is a racist, a point stressed last week by the Pulitzer-winning biologist E O Wilson, of Harvard University. In his autobiography, Naturalist, Wilson originally described Watson, fresh from his Nobel success, arriving at Harvard's biology department and 'radiating contempt' for the rest of the staff. He was 'the most unpleasant human being I had ever met,' Wilson recalled. 'Having risen to fame at an early age, [he] became the Caligula of biology. He was given licence to say anything that came into his mind and expected to be taken seriously. And unfortunately he did so, with casual and brutal offhandedness.'

That is a fairly grim description, to say the least. However, there is a twist. There has been a rapprochement. 'We have become firm friends,' Wilson told The Observer last week. 'Today we are the two grand old men of biology in America and get on really well. I certainly don't see him as a Caligula figure any more. I have come to see him as a very intelligent, straight, honest individual. Of course, he would never get a job as a diplomat in the State Department. He is just too outspoken. But one thing I am absolutely sure of is that he is not a racist. I am shocked at what has happened to him.'
I especially find Wilson's remarks revealing, because Wilson has always been known to be a compassionate, fair and objective scientist who would be loathe to offer unabashed support for pet ideas and people. I have read several of his books and never have found him to be biased or narrow-minded. I think that him saying something like this about Watson, a man who was his bete noire for years, surely says something. And Wilson's depiction of himself and Watson as the two grand old men of American biology is quite accurate. The two grand men made a rare appearance on Charlie Rose quite recently.

"Don't silence the scientists"

Susan Blackmore's quips on Watson and academic freedom. Particularly sensible is this:
Surely a society based on denying a possible truth is not a healthy one. If there are such differences we need to be absolutely clear that they do not mean that some groups are intrinsically inferior, superior, or more or less deserving. If it is true that children of different races, by and large and on average, differ in their abilities, then we need an education system that encourages and develops all those varied abilities rather than one narrowly and rigidly based on glorifying the particular kind of intelligence and academic achievement that comes more easily to the dominant group."
I am not so sure that cancelling his lecture at the Science Museum was uncalled for; I see it more as an angry rap on the old man's hand. On the other hand, I now am agreeing that suspending him from his CSHL job does not serve much of a purpose, and reflects badly on respecting academic freedom. After all, institutions have been known to distance themselves from their employees, especially academic ones, and most people don't equate institutions' opinions with those of their employees. For example, should MIT fire Noam Chomsky because he has sometimes espoused what some have claimed as radical and bigoted views? Of course not, and here the issue clearly is about academic freedom. If Lehigh University can simply get away with putting a disclaimer on their site distancing themselves from Michael Behe (whose creationist leanings are much more crackpot than even Watson's, if not as offensive-sounding), then why can't CSHL?

Kornberg goes nano

Roger Kornberg is a remarkably versatile man. After the discovery of the structure of the gigantic transcription RNA polymerase complex that bagged him a Nobel Prize last year (and brought in shouts of "No chemistry Nobel to a biologist!"), he has now unravelled the structure of a gold-thiolate cluster at the exquisite resolution of 1.1 A, clearly a more "pure" chemistry achievement. The paper made the front page of this week's Science and has been called a tour de force.

For anyone liking crystals this will be delicious. The pictures in the SuppInfo are even better. The structure may lead to a revision of other previously thought structural notions.

Commentary
Paper DOI: 10.1126/science.1148624

When scientists get old and boring...

James Watson has turned from provocative and scientific to racist-sounding and irrational. A pity...

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Paradise regained?

It should be a resounding slap in the face of global warming contrarians, now that Al Gore and the IPCC have won the Nobel Peace Prize:

"for their efforts to build up and disseminate greater knowledge about man-made climate change, and to lay the foundations for the measures that are needed to counteract such change".

Now of course, that does not mean all our problems are solved, and that policy will now proceed smoothly. Fox News and others will still find good excuses to discredit the prize. They will probably even say that the prize makes Al Gore an even richer man while the rest of the world grows poorer. They will also speculate about the gratuitous lobbying that went on in their opinion in the deliberations. In addition, falling back on Gore's personal lifestyles is an argument which they could never let go of. Whatever.

The prize was expected and it's probably not very surprising even if a happy circumstance. There are still miles to go before we bring carbon emissions under control though, and even if we stop today, many deleterious effects will continue to be observed, and curbing those effects is going to be a complex scientific and political process. In fact, the prize also does not mean that climate change is now suddenly fully understood. But this is at least a partial vindication.

What I feel happiest about is not just that the Prize was awarded to Gore and the IPCC, but that it was also awarded to those thousands of scientists, who starting in the 1950s travelled to the farthest reaches of the planet to drill ice cores, document effects on sea level, snow cover, wildlife habitats and human populations. It's also a big thank you to those like James Hansen who have tirelessly worked in the face of political suppression to build computer models and relentlessly weed out the uncertainties (especially those caused by forcings). In fact, in my opinion Hansen himself deserved this prize, but it may been unfair to some other scientists.

Awarding one half to the IPCC for "building up" the scientific background of climate change and the other half to Gore for "disseminating" this knowledge seems like an apt split. The IPCC has constantly published reports since 1989 on climate change. It's latest report in 2007 was an encapsulation of cutting edge research and the most current conclusions it has drawn, which have not changed substantially from the 2001 report. The main contribution the IPCC has made between the two reports is to weed out uncertainties caused by "forcings"- factors including artificial ones like fossil fuel emissions and aerosols and natural ones like volcanic emissions that can either increase or decrease global temperatures. The problem previously was that some of these factors, especially those decreasing temperatures, had large uncertainties and so their potential balancing impact on CO2-induced warming could not be evaluated well. However, much progress was made between 2001 and 2006, and in its latest report the IPCC concluded that the "negative" forcings were much less than what was needed to counter the "positive" forcings. I would strongly suggest reading the IPCC summary. Anyone who reads it and still strongly suspects global warming needs to have immediate access to a dictionary and the mental asylum.

This is the first Nobel Prize for climate change as such, but it should be noted that one was given earlier for Chemistry to scientists who discovered the destruction of the ozone layer by CFCs. That research was a resplendent example of how science can starkly reveal the effects of human activities on the environment and force everyone to reconsider their way of life.

On the political front, George Bush and his yes-men can now do nothing more than concede to the grim reality of climate change, although it will be hardly surprising if they still don't. A couple of months ago, Bush stood in the White House Rose Garden and endorsed the 2007 IPCC report and human contributions to climate change. As Chris Mooney points out, he could have done exactly the same thing in 2001, when much of the science was equally well-known. But politicians and especially the current administration thrive on uncertainties in a perverted manner; while scientists thrive on uncertainties because they will improve understanding, politicians thrive on the same uncertainties so that they can cherry pick and try to discredit the entire enterprise.

The beauty of science however is that it always continues to progress, through mistakes as well as triumphs, and this is a fact which thwarts even the most powerful politicians' motives. Even if men in power can score temporary political points by discrediting science, they forget that science has simply retreated beyond the stage, where it continues to march on through the tedious work of dedicated scientists. This exact same principle applies to any other heavily politicised scientific debate, including the nonsense about creationism. As the eminent biologist Francisco Ayala says in his book about evolution, it does not really matter for science if creationism is taught in schools or whether anyone thinks evolution is a conspiracy, because research in evolution will always continue to advance our understanding irrespective of policy. Biological research on homosexuality will continue oblivious to the debate about gay marriage. Research on the benefits of stem cell therapy will continue oblivious to whatever veto the President enforces. Science will continue to thwart the contentions of conservatives about life beginning at conception. Science does not and will not care about the vagaries of politics and spin. And the heart of the reason for this inexorable flow of science is that while politics is about the affairs of humans, science is about factual truths about the world. Its course may be temporarily modified or even stopped in the rare circumstances where unreason triumphs over all (such as in the trial of Galileo), but we can be more than rest assured that since discovery is a process inherent in the history and future of the world, this process will never ever abate. Not just this prize but all vindication of climate change is a vindication of the character of science which will always progress, and we should be thankful for those scientists who keep on quietly working behind the curtains on this progress.

So there is it; the first Nobel prize for climate change. In my eyes, the biggest vindication more than anything else has been about the science. People should yet again be convinced now that the science, with all its uncertainties, is still founded on a solid basis, and this in fact goes to the heart of understanding the scientific process itself. Let's hope that the prize causes even more public awareness than before, especially on an individual basis. Combating climate change will involve changing human nature a little, and that seems impossible. But as Spencer Weart says in his excellent book on global warming, CFCs provide a good example of how humans can change deeply-rooted practices and profit making in the face of impending problems. Global warming is a bigger problem. It will just take bigger efforts. I don't see why we cannot do that.

Previous posts related to global warming and climate change: 1 2 3 4 5 6 7 8

Interview with Brian Shoichet: aggregation-induced inhibition

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Ok, now that we have gotten past the Nobel mania (or maybe not; go Somorjai), we can hopefully come back to real life. I was reading an interview with Brian Shoichet, who is one of the most promising stars in the areas of screening, docking, and structure-based design. He has gotten his fingers in many pies, both computational and experimental.

However, it was somebody's comment about the pharmaceutical industry thinking that "Shoichet deserves a heroes prize" that got me looking at his work, and I quickly learnt the reasons for that quote. As we all know, one of the biggest or perhaps the biggest problem facing HTS in industry is false positives. A lot of times, molecules that are found to be active in an assay fail to be active later. If industry could weed out such nuisances ahead of time, a lot of time, money and energy could be saved.

Shoichet, after a lot of interesting initiation and investigation, came up with one simple reason for why molecules may be showing false colours; because they form colloidal aggregates that somehow inhibit the proteins in the assay. If these are broken up say with detergent, the individual molecules no longer show activity. Thus, a relatively simple physical phenomenon is responsible for these molecules showing false activities. Such molecules were detected in earlier assays by some characteristics, mainly very steep dose-response curves and flat SAR; changes in structure usually causing very small changes in activity. They are also often promiscuous inhibitors. But nobody knew what was exactly happening and all the analysis was post-"mortem".

The first step in Shoichet's lab was the elucidation of this aggregation-induced inhibition. The aggregation can be detected with dynamic light scattering (DLS). The more challenging and useful step is to be able to come up with a list of chemical scaffolds that are likely to show this phenomenon, so that one can watch out for them beforehand. Before that, one would also need to know the exact mechanism of aggregation-based inhibition. In case of some molecules, there is some structural correlation, flat aromatic dye-like molecules being prone to aggregation for example by stacking. But many other scaffolds seem more diverse and at first glance show no common functionalities. Ths phenomenon is linked by common physical forces, not chemical ones. The details are not known but continue to be worked out.

Shoichet's lab continues to make progress, and he has recently come up with a screen for detecting such aggregation-based inhibitors (DOI: 10.1021/jm061317y). There are two major conclusions from the study; first, that breaking up aggregates with detergents can be a good way of identifying them, and secondly that aggregation may be a much more common phenomenon for false positives in screens than was thought before. This fact may be extremely significant for industry and could potentially save a lot of time, money and labour beforehand.

In other quite different work (DOI: 10.1038/nature05981), Shoichet also made the cover of Nature, when he used docking and structure-based design to predict the function for an enzyme whose function was unknown, based on substrate docking and analysis. The strategy used was quite clever; docking thousands of high-energy forms of metabolites rather than the metabolites themselves to know which ones would optimally interact with the active site. In this particular case, the "optimum interaction" pointed to a deamination, and the protein of unknown function indeed experimentally turned out to be a good deaminase.

All in all, a very promising chemist and I believe one to watch out for. Unfortunately, the interview itself is published in the journal Assay and Drug Development Technologies, not one which libraries usually subscribe to (I got it through ILL). But here's the DOI anyway (DOI: 10.1089/adt.2007.9996)

Also, again, check out his Colbert-style interview on youtube.

Ertl gets the Nobel, but Somorjai?

And the prize was awarded to German physical chemist Gerhard Ertl for his study of reactions at surfaces. The prize seems well-deserved, but it also seems to be awarded for the general field of surface chemistry, which leaves me (and many others I think) very surprised to say the least that Gabor Somorjai did not share it, especially also considering the fact that the two shared the Wolf Prize together. To my knowledge, Somorjai has been an absolute giant in the field. Compellingly weird.

Well, at least the prize went to a bonafide old-fashioned "chemist" this time.

Addendum: Thinking about it more, I think the Nobel Prize committee really blew it this time. This is because Somorjai is really THE obvious and preeminent candidate for a general prize in surface chemistry. He is heads and shoulders above everyone else in the field in this regard. In this particular situation therefore, the exclusion is glaringly obvious, and I think the committee is going to take a lot of flak for it.

2007 Chemistry Prize: last minute revision

Sorry, but the Nobels have somehow been a minor interest of mine for a long time. I like to know about Nobel stats the way baseball fans like to know about their sports's stats. While I have already listed my thoughts, I also have some personal favourites. These are folks who either work in my field(s) or whose work I have known about for a long time and admired. I also liked the colour of their sports jackets.

Martin Karplus: The doyen of theoretical and computational chemistry, especially as applied to biological problems. More than anyone else he influenced the field

Stuart Schreiber: Great pioneer of chemical genetics. Great life story and again the dominant influence on his field.

J. Fraser Stoddart: Need toys get some from this guy. Sometimes though, his work sounds like too much fun to get a Nobel Prize ...

Ronald Breslow: I have always loved to read about his work. Chances do look a little slim, but a general prize for biomimetic chemistry missing him would be sacrilege. It might miss others though. I am thinking that Ron Breslow being awarded might make both the "pure" and "impure" chemists happy.

Harry Gray: Gentle, unassuming giant of a man. His work on electron transport in proteins is spectacular and I was very impressed when I read about it. Might be a little premature. A general bioinorganic prize might include him and Stephen Lippard. Again, many other contenders, and field may be too general.

Personal favourite fields for Nobel contention: chemical biology, crystallography, medicinal chemistry, computational chemistry, nanotechnology

And Al Gore for detecting anthropomorphic changes in the ozone layer.

In general, I will be happy if anyone who might be called a "chemist" without too much head-scratching gets it. I also realise that the probability of knowing about a correct potential winner would correlate with the number of bloggers in diverse chemical fields who make predictions. At this stage, we have a bunch of bloggers from almost every field of chemistry here who know the biggies in their field who they then can write about for the others' benefit. Thus, one might think that between all our blogs, we have potential "winner space" covered. Nonetheless, last year can only be a sobering lesson, when not a single blogger could predict Roger Kornberg winning. However, we can argue that perhaps it was because there weren't many molecular biologists blogging who could have made that prediction. Since the possibility of a "pure" chemist winning this year seems higher, I am keeping my fingers crossed that at least one of the blogs made the correct prediction.

Now, fight! Till tomorrow.

P.S. Damn...there should be some remuneration for correct predictions.

P.S.2 Last second addition: Albert Overhauser

2007 Physics

This year's prize goes for that-thing-about-which-I-have-heard-but-never-read-up-on. If I have heard about GMR many times but don't know anything about it, it surely must be Nobel-worthy. Compliments to Albert Fert and Peter Grunberg.

Now waiting for tomorrow...

Turning a false-positive into an active

People who deal with molecular recognition are well aware of what difference a small modification to a molecule can make. Just today I was attending a talk by a chemist who binds small molecules to RNA aptamers. He showed an aptamer that binds theophylline with 10,000 fold more affinity by caffeine- a huge difference in binding affinity for a molecule differing by only one methyl.

So it is also for medicinal agents, as demonstrated below for an example from the cited study. People who do screening must always have this nagging doubt about false positives; what if there is only a slight modification to a false positive that will convert it into an active?

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Bill Jorgensen's group has done a similar study for an anti-RT HIV inhibitor. He first did similarity searching with the Maybridge library based on six known NNRTI inhibs of RT. Based on this, he found a couple of molecules in the library which he then docked into the active site of RT using the program GLIDE. Along with the six known inhibitors which scored at the top as binders, he also found one from the library. GLIDE had already been benchmarked by reproducing known crystallographic conformations.

However, when they tested this GLIDE ranked molecule against HIV, it was disappointingly inactive. On the other hand, perhaps, since GLIDE had docked it up there with the known actives, there might be a small modification that one could make to it which would inject some activity in it? Jorgensen's group used a program that they have developed named BOMB, which basically docks a molecule in an active site, and then grows appendages to it to see if it would make a difference in the binding affinity. BOMB tried out combinations of different groups on the phenyl ring of the molecule, scored the resulting structures using its energy function, and finally settled on one particular modified structure- also filtered by logP values and other Lipinski considerations- that eventually gave an IC50 of 300 nM. Not a fantastic number, but good enough to pursue as a lead.

Also noteworthy in the paper is a short discussion of another publication where a similar structure was published. According to the authors, the other authors assayed the wrong compound. Heh.

Reference:
From Docking False-Positive to Active Anti-HIV Agent
Gabriela Barreiro, Joseph T. Kim, Cristiano R. W. Guimarães, Christopher M. Bailey, Robert A. Domaoal, Ligong Wang, Karen S. Anderson, and William L. Jorgensen
Web Release Date: 06-Oct-2007; (Article) DOI: 10.1021/jm070683u

2007 Medicine Nobel

Knockout mice...now why didn't I think of that in my prediction post? Seems at least one of them was explicitly a contender for the prize even in 2004 as considered by Nature.

Miles to go before...

A recent and highly promising trial of an HIV vaccine has failed and shown depressing results. This setback reminds us of how complex a problem HIV/AIDS is, with so many daunting scientific, economic, political and sociocultural ramifications...

Read the rest of the post on Desipundit...

Fluorine in pharmaceuticals

Among the lessons which I learnt in graduate school was another important one: organic fluorine rarely forms hydrogen bonds. The layman's explanation for this phenomenon is that F holds tightly on to its electrons and does not share them.

However, there are enough number of examples among protein-ligand interactions, although much fewer than the other ones, to warrant attention to the role of F in drugs. The review in the latest issue of Science does exactly that. (DOI: 10.1126/science.1131943)

Some of the salient points I got from this and other reviews:

1. F as bioisostere: As is known, because of its similar size, F can be a good bioisostere for O, and C-F bonds can stand in for C-O bonds. The review mentions C-CF3 as substitute for C-O, and vinyl C=C-F as substitute for peptide bonds. The introduction of F can considerably alter conformational preferences. The review mentions the interesting case of O-CH3 vs O-CF3 bonded to an aromatic ring. In the former, the group is in the plane of the ring because of pi-orbital conjugation with the ring, whereas in the latter, O-antibonding C-F orbital conjugation destroys this preference and swings the group orthogonal to the ring.

2. F as acidity promoter: It is well-known that F increases the acidity of amines. In some cases, one can decrease the pKa to below 7, so that the amines will not be protonated at physiological pH. This can have the consequence both of improving permeability by increasing the neutral form of the amine, and radically changing the binding mode. A remarkable example is of a series of thrombin inhibitors, where the pKa could be decreased from 10 to <2 by introducing well-positioned Fs. I have already talked about the exceptional case of 3-F piperidines.

3. F as lipophilicity enhancer: Another important property of increasing the logD value. The review also mentions cases where the logD actually falls. F's lipophilicity has been famously incorporated into Teflon®, and hexafluoroisopropanol and hexafluoroacetone are often used to enhance alpha-helical content of peptides on the basis of this property. Balaram and Rajan have argued that these solvents actually "dry" the peptides ("Teflon coated peptides")

4. F as H-bonder: A unique property of this chap. I always remember a review by Dunitz in which he statistically examined a large number of CSD entries and found an exceedingly small number of cases where organic F could be a bonafide H-bond acceptor. However, there are also cases, where F in ligands shows close proximity to C-H, N-H, and most interestingly, C=O bonds where F interacts with the carbonyl carbon. This is in contrast to the recently investigated "halogen bonds" where Br and Cl seem to interact with carbonyl oxygen in proteins.

Clearly, F's behaviour in enhancing protein-drug interactions is valuable. And it remains as interesting and enigmatic as ever. An always colorful beast.

2007 Nobel Prizes

A couple of nights ago, I had a curious dream. I dreamt that Stuart Schreiber has won the Nobel Prize for this year, and I remembered that exactly one year ago, I wrote a post about predictions for the Prize. None of the ones I thought about got it of course, and in the end, someone who nobody thought of- Roger Kornberg- got it. In retrospect, it is not too surprising. At the time as many bloggers would remember, much noise was made by people including myself that a "non-chemist" has won the chemistry prize. In retrospect however, the prize seems quite deserving. Kornberg always made it clear in interviews that he always thought of himself as a chemist, and his tremendous achievement was to reduce a dazzlingly complex and extremely important biological problem to a chemical one which he then meticulously solved. All kudos well-deserved.

This year, I don't have much to add to my last list. Interestingly, there are a few who I could think of possibly taking off the list. David Baker for example whose work may not only be premature, but is thought by some to be less impressive than what it is. I personally am not so sure about George Whitesides either; not that he has not done spectacular work, but he seems to be deserving more of a lifetime achievement award for many varied contributions, something that the Nobel has been relatively rarely awarded for. That's why I am not sure about Martin Karplus too. Ditto for Stephen Lippard, Harry Gray and the bioinorganic chemistry cabal.

Then there are others who in my eyes now seem to be deserving the prize even more. Stuart Schreiber should really get it in my opinion. J. Fraser Stoddart, Roger Tsien, and people from the single-molecule spectroscopy field also are top of my list this year. As it was last year, Roger Tsien would surely be a perpetual favourite in light of the sheer number of applications his discovery has found.

It would be perfectly plausible for x-ray crystallographers to get it for structures of say the ribosome. Bacterial rhodopsin also may deserve it. But it's unlikely only because a similar one was given out last year. As for pure organic chemistry related stuff, the palladium reaction guys still seem to have a chance, except for the fact that a methodology prize was given out two years ago. An organic related prize should be awarded to organic-chemists-turned-chemical biologists like Schreiber and Schultz.

Folks from the materials science legions are also increasingly deserving, and just like last year, I feel almost sure that the prize would be an interdisciplinary one awarded to either nanotech/materials or chemical biology. I already mentioned Stoddart. Robert Langer from MIT also seems to be in line, perhaps for medicine. I am not really aware of people in the organic electronics area who could also get it. That could be premature, but Jan Schon definitely won't be up for it.

Another class of people which comes to my mind for the Medicine prize is that of researchers involved in discovering key signal-transduction molecules. Maybe Nf-kB, maybe TNF, maybe some other universal regulating or transcription factor. Others also seem to be likely candidates for the Medicine prize. What about Judah Folkman who proposed angiogenesis as an organizing principle in tumorigenesis? Or perhaps the guys who advanced the amyloid hypothesis?

"Techniques" prizes also seem likely as usual. RNAi already got it. So have MRI and applications of NMR and Mass Spec. It's hard to think of any other prominent recent technique but I may be missing something key in analytical chemistry/molecular biology.

Could we conjecture that some old guy/woman would get it? If we look at the age statistics of Nobelists, it's quite clear that the age of young Turks getting the prize seems to have been declining. Maybe it reflects on the considerable education and groundwork that a researcher has to get rooted in before he can make significant contributions. The average age at which a new researcher gets his first big grants also has gone up. On the other hand, one can be grateful that applied fields like medicine are, unlike pure mathematics, not a young person's game.

In any case, this is always an interesting time of the year, and it's always a really nice feeling to see someone whose work you are familiar with and praise, peering at you from the website and lending his views to a telephone conversation. And it is always fun prognosticating, just like a small kid ranking his GI Joes using different criteria. And just like GI Joes, in the end, it is best to walk away and not make a big deal about it.

Paul and Derek also have lists from last year and this year.

Lomborg on Maher



The economist Bjorn Lomborg appeared on Bill Maher last Friday. As some may know, Lomborg is one of the more well-known global warming skeptics in the world, and became persona non grata in many scientific and policy circles after publishing his controversial book The Skeptical Environmentalist in which he spoke spiritedly against global warming.

Now Lomborg has come out with another book disarmingly titled "Cool It: The Skeptical Environmentalist's Guide to Global Warming". As in his earlier book, Lomborg's basic thesis is not that man-made climate change is unreal, but that there are more pertinent problems to solve in the world, and one has to think about the issues in a rounded manner before deciding where to spend money to cause the optimum effect.

I think his way of thinking is legitimate, but I don't agree with it. However, I think Maher and Salman Rushdie probably castigated him a bit too much after the interview. At least in the interview, it did not seem that Lomborg was actually denying global warming, but was trying to ask that all the effects of climate change, positive and negative, should be evaluated as a sum total. In fact, he even admits that the bad effects of climate change may outweigh the good ones. Clearly, Lomborg is a very smart and articulate guy, and I don't think he is dumb enough to just negate global warming.

But what I find most disingenuous in Lomborg's argument is his assertion that all that money spent on climate change could be more productively channeled into more pertinent problems, like AIDS, poverty, and infectious diseases. What I want to say is this; you want to look for a source from which to funnel unproductive funds into these problems?? Please think of the war in Iraq. Or think of the myriad other ways in which governments and especially the US government spend taxpayers' money. If you want to spend money on these undoubtedly important problems, why pick on climate change to do it? At the very least it's disingenuous and ignores other massive sinks of crucial money in the world, and in reality it is a travesty because you want to sap funds from something that's obviously critical for future generations.

On a related optimistic note, more people from various countries now seem to think that climate change overall is bad and that humans are contributing to it.

Three lessons

When you have been in graduate school for two or three years, it's a good question to ask which are the important lessons you have learnt from your time there. These are not the "lessons of life" I am talking about- they are perhaps even more important- but technical lessons which spring to your mind. In my case, three lessons strikingly come to my mind. All of them are related to work that our group has done, but also to other people's work and general thought. All of them deal with material published in the literature that is unfortunately "fiction", and articles in journals don't seem to acknowledge this fact. Here they are:

1. Oxidation states for transition metals greater than 1 (eg. Au3+, Cu2+) are fictional and non-existent (related post and references)
2. Single "average" structures derived from NMR for flexible molecules are fictional and "virtual" (related post and references)
3. 3-fluoropiperidines exist in solution almost exclusively as the axial-F conformer. (related post and references)