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)

The Open Society

I am having a fantastic time in London. Details later, but what struck me the most is the incredible friendliness, helpfulness, and most importantly open-mindedness of everyone we met. A large group of people whom we met consisted of doctors and clinicians who are directly involved with cancer patients. I was surprised and very happy to see that these people, with little to no experience with synthesis or modeling, were extremely open to collaboration including both these disciplines.

This is exactly the kind of culture we need to see to fight cancer and other ailments, where everyone from doctors to modelers to synthesists to materials scientists and engineers seamlessly work together and are open to collaboration. Also, nobody but a doctor can truly understand what impact a new treatment can have on a disease. One of the doctors we met had just seen a patient, a young lady not more than 35. He told us that he did not expect her to live much longer. Faced with morbid scenarios like this on a regular basis, it should not be surprising if doctors are willing to try anything and everything to make a new treatment available to patients. And yet it is rare to find people having an untrammeled vision of collaboration, which made our experience a truly pleasant one.

This sort of reminds me in a different sense of that saying which says that strangers are simply family members who we have yet to meet.

O, and kinases were definitely everywhere in the air :)

Queen and country and all that

As an anglophile, I am excessively excited about starting on a trip to London tomorrow evening. I am travelling with my advisor, and only hope that we don't sit next to each other on the flight...just kidding; I am sure that my advisor would be one of the few advisors who don't make for an awkward conversation partner on a plane. Plus, this is one of the few times that I would get to make sure that he listens (or at least pretends to listen) to my boring talk about career aspirations (or the lack thereof), the beneficial effects of crystal meth (knowledge gained purely through armchair cogitation), the droll charm of 1950s textbooks, petty rivalries between staid Nobelists, and family values in the cultural strongholds of Pune. But most importantly, he has agreed to review my manuscript on the flight! At last, after months of playing cat and mouse, I have him cornered.

While we will be there for a business trip to meet with our collaborators at Imperial College in London, I am of course going to take every opportunity to explore the place where everything from stones on sidewalks to statues to fountains to tailoring shops has sometime seen the presence of Darwin, Nelson, and Shakespeare. For any history lover, London would be a cornucopia, and while I know I won't be able to get enough of it in one week, I hope to hungrily mop up whatever I can.

Also, my friends there have promised me to get me drunk in some exquisite English pub. Ther are Germans studying in Britain, so I can hardly doubt their ability to imbibe unheard of quantities of ethanol (I knew it was a mistake to offer one of them a treat to drink "as much as he wanted" when he was here...). But in any case, since I don't drink and they are honourable men, I am sure they will be content to let me contemplate the composition of 400 year old English pub table wood. And I do hope they bring their wives along to keep them from going overboard. Behind ever pub man, there is a woman, to catch him when he falls back.

Trad med and all that

Curcuminised Chicken

Two articles in the latest issue of Cell are on the value of traditional medicines in modern drug discovery and organic chemistry. They focus on things like artemisinin, curcumin etc. and especially curcumin. The articles talk about efforts in India and abroad to harness the immunomodulatory and other powers of curcumin. Noteworthy is how an early patent on curcumin actually prevented its future therapeutic development:

"Even as publications on curcumin’s effects on cell lines and in animal models of disease increase dramatically, there are only 13 clinical trials underway worldwide. Part of the delay is attributable to a US patent, granted in 1995 to researchers at the University of Mississippi Medical Center for curcumin’s wound-healing properties, that prevented its development as a therapeutic. In a landmark case, the Indian Council of Scientific and Industrial Research (CSIR) spent two years arguing and finally proving that curcumin has been part of the Indian traditional system of medicine for centuries and that this knowledge should be considered “prior art” and hence in the public domain. The patent was finally overturned in 1997."

I will leave it for the patent pundits to opine on this one, but it seems to me that indiscriminately patenting trad meds can foreclose further development of their promising benefits. There is of course a point further down the line when patenting would be necessary.

The reports say that because curcumin is not patentable, there has been limited pharmaceutical interest until now, and only solid clinical data can pique their curiosity. The generation of such data seems to be looked into seriously now. One of the major problems with curcumin of course (looking at the structure) is its water insolubility. Some nanotechies are trying to get around this problem using polymer coated nanobeads.

Curcumin of course inhibits NF-kappaB and this has been validated. But NF-kappaB is everywhere! So I am skeptical of the number of cases where curcumin can actually take advantage of the window of safety that can be exploited. I of course eat curcumin almost everyday, but I haven't gotten my kappaB levels checked recently. Curcumin has also been implicated in interaction with COX-2. Thus, it has been binned to have potential anticancer and anti-Alzheimer's properties. In any case, even if I don't die from AD or cancer, I will die from something else. So it doesn't really matter. LPI has a long list of benefits and studies on curcumin. The Cell reports also say that curcumin may actually be inhibiting Ikß kinase and not NF-kappaB directly. But the versatility of curcumin also makes fine-tuning and probing its activity more difficult. That is where pharma with its myriad facilities, brains, and funding will have to come in.

But the reports are encouraging because they make it clear that Western interest in Eastern meds is seriously rising. After all, considering the number of drugs we have gotten from fungi, soil microorganisms, and marine sponges, this sign can only be a good omen.

We all live in a yellow submarine.

References:
1. From Exotic Spice to Modern Drug?
Seema Singh doi:10.1016/j.cell.2007.08.035

2. Molecular Understanding and Modern Application of Traditional Medicines: Triumphs and Trials
Timothy W. Corson and Craig M. Crews
doi:10.1016/j.cell.2007.08.021

Plagiarism Inc.

Sad:

"The trouble began last November, when Salti and another graduate student, Oktay Aydogdu, underwent oral examinations for their PhDs. Although both had an extensive list of publications in gravitational physics, they struggled to answer even basic, high-school-level questions, according to Özgür Sarioğlu, an associate professor at METU. “They didn’t know fundamental stuff like newtonian mechanics,” he says. Suspicious, one of Sarioğlu’s colleagues, Ayşe Karasu, began to look through the duo’s publication record. Using Google, she quickly turned up a paper from which it seemed the students had lifted several lengthy sections. By mid-February, faculty members had identified dozens of articles on arXiv that they say seemed to be partly or completely plagiarized."

Even sadder:

"Katepalli Sreenivasan, director of the International Centre for Theoretical Physics in Trieste, Italy, which has a programme of collaboration with physicists from the developing world, agrees. “There are some cultures in which plagiarism is not even regarded as deplorable", he says.

The scale of the plagiarism also seems to be huge; 70 papers in all penned by 15 authors. Peter Woit has a list of all the journals and articles.

When it comes to plagiarism, I always have some thoughts:
1. A lot of researchers who publish low-level or relatively less important work are tempted to plagiarise because they feel fairly sure that very few people, if any, will check their work since it's not high profile. Consider a researcher at some obscure Turkish university. He knows that he is not going to win a Nobel Prize. But he thinks that he can slip one (or many) through, and then by sheer number of publications, can get a tenured position in some Turkish university and have job security for the rest of his life. If inexcusable, it's not that hard to understand the temptation and the logic behind such thinking. The dilemma of detecting such plagiarism is really a riddle of the age of information explosion. Who has the time to plough through the thousands of articles published every day, especially if only 1% of them are non-trivial?

The real burden here is on the referees and the journal editors, and a large share of the blame does belong to them. But even there, I can sympathize with the scores of fact checkers who, deluged with so many papers that are keeping them away from their real work, simply have to take a few pieces at face value. Nobody can confirm everything he or she receives. Unless there is some glaring discrepancy, there is usually no need for a referee or editor to check and triple check every single fact. There must be some space for trust and faith in paper submission and evaluation. However, there are also some papers that do have glaring discrpancies and holes, which still manage to get past the editors and referees. In such cases, the blame does belong on their shoulders.

2. On the other hand, that makes me find the antics of people like Hendrik Schon astonishing. How can they think they can get away with publishing so many groundbreaking-sounding papers in such high profile journals, when dozens of researchers will pounce on them and scrutinize them and try to duplicate the results?

The scariest graph I have seen in a while

It says it all.

The article is worth reading (doi:10.1038/442736a)

Freeman Dyson (1923-): Vignettes in science- 1

Read the entry on Desipundit...