Right mind at right place at right time

"But at the time, there were many smart people doing physical organic chemistry and there was this new field called organometallic chemistry. There were few people looking at the mechanistic side and it looked like an area where you could take the tools of physical organic chemistry and solve problems. Plus, it looked like it could be a good way to make new reagents for organic reactions. And you could get into the field real fast - you only had to read three papers and you were an organometallic chemist!"
Interview with Bob Grubbs.
Ah, the good old days...I wonder what field is like that right now...

I have incidentally seen Bob Grubbs talk and interact two times, and he does not fit the image of the distinguished Nobel Prize winner at all. Very simple, unassuming, straightforward, friendly guy.

The making of Darunavir

Image Hosted by ImageShack.us

Arun Ghosh at Purdue has written a review (Ref. below) of his group's development of Darunavir, the novel bis-THF containing HIV protease inhibitors. For some reason, I find this work very nice, both for its rational nature, and for the novelty of the structures.

It's interesting that the work started from a simple premise; that inhibitors targeting the backbone atoms of the protease would be effective across many mutant strains, as the virus cannot really afford to change these residues without serious problems. As with other hypotheses, this was easier stated than proven, but the targeting of two backbone Asp residues in the protease through hydrogen bonding with the bis-THF turned out to be a neat and predictable strategy. Ample crystal structures confirmed this.

Some of the nibs show crazy IC50s (4 pM for one of them). Darunavir (16 pM) was approved by the FDA in 2006. As far as I can tell, the synthesis too looks simple and facile.

Really nice example of rational drug design in my opinion.

Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance
Arun K. Ghosh, Bruno D. Chapsal, Irene T. Weber, and Hiroaki Mitsuya
DOI: 10.1021/ar7001232

Water-inhibitor synergy in CDKs

An interesting paper published in the J. Chem. Inf. Mod. investigates the role of water molecules in CDK2 and CDK5 active sites. The authors use MD simulations to simulate water and inhibitors (in this case the well-known indirubin analogs) in the active site of the CDKs. The interesting observation they make is that in some cases, the inhibitor "recruits" a water molecule to form a bridged interaction with an atom in the protein, thus achieving the "correct" binding mode. In other cases, blockage of the active site by a loop prevents this water grabbing trick.

The study also highlights how it can make a big difference between using monomeric CDK and CDK bound to a cyclin when simulating nib ("nib": inhibitor...apparently new yippie slang) binding. In this case, the difference is in the water recruitment.

Again, one is reminded of the many subtle factors, including water interactions, that dictate differences between nib binding to different but similar kinases.

H for?...

Philip Ball writes about the Hirsch h- index which is in fashion currently to predict the productivity and impact of researchers. in a nutshell, a scientist who has a h-index of X is one who has published X papers with at least X citations each. One has to say that the h-index does look better than some other indices, trying to encompass both quality and quantity. On the other hand, it does leave out some prominent names.

For me, the h is like the Nobel Prize; those who have a high one are almost without exception really good, but there are so many who are not in the top twenty who are also noteworthy. For example, what about Oliver Lowry, who is the most highly cited researcher ever, for his discovery of the folin phenol reagent in biochemistry? Or what about Canadian Axel Becke, whose paper on improved density functionals is one of the most highly cited papers ever, and the most highly cited one in the last twenty years (I believe). Also consider the fact that his functional, instantly recognisable to theoretical and other chemists in "B3YLP" (Becke-Yang-Lee-Parr) is ubiquitous in structure calculations in every branch of chemistry.

The problem with the h-index of course is that it does not recognise flashes of brilliance or contribution which have become ubiquitously used in the field. Just like many other indices of recognition, it leaves aside discoveries which in terms of utility are very important, but which in terms of novelty may not be regarded as stellar. Maybe their originators won't get Nobel prizes, but in some ways their contributions are equally "important". What about Charles Pederson who discovered crown ethers (although he did get a Nobel)?

However, in the end, the h-index like any other index fails, because it aims to be a quantitative indicator of "greatness" or "importance", and at least in people's minds, tries to say which scientist is more or less important or greater. Some scientists like E J Corey are obviously important or great. But others like the ones above are also pretty important, but this is not captured in the h-index.

Nonetheless, I think the index is probably the most reasonable citation system that has come out in many years.

Who was smarter?

Compared to Richard Feynman, Murray Gell-Mann did not get the popular appreciation he deserved...

Read the rest of my post on Desipundit...

Path-y-ological science: Homeopathy and the memory of water

Inspite of its anecdotal benefits, homeopathy has rightly been regarded as dubious science. Especially its strained hypothesis of dilution actually increasing the potency of a drug runs counter to established scientific principles. But anecdotal evidence and good faith continues to fuel the homeopathic establishment. A novel hypothesis to explain the basic principle of homeopathy- the "memory of water"- was long discarded. Unfortunately, it seems to be getting credence once again. The new debate, however, establishes no basis for believing in this fantastic idea...

...Read the rest of my post on Desipundit...

Another joy

Some time back, Paul had listed reasons for why someone would want to become a chemist. I realised one more; you get to hear about exotic books, journals and universities. And this of course applies to all the sciences.

We are analysing the conformation and solution behaviour of an alkaloid, and we ran into some trouble because the molecule seemed to decompose in solution. While investigating possible reasons and pathways for why this could happen, I discovered (or rather, rediscovered) Manfred Hesse's splendid Alkaloids: Nature's Blessing or Curse? This is a lavishly illustrated book about the history, synthesis, biosynthesis, and uses of alkaloids, with hundreds of colour photographs of alkaloid chemists, plants, and flowers. Then, while investigating the pathway elucidated in the book further, I came across a relevant paper from the Collection of Czechoslovak Chemical Communications. And finally, a colleague sent me another relevant paper from a group at Semmelweis University whose name I had not heard before...this of course reminded me of Ignaz Semmelweis, the Austro-Hungarian doctor who pioneered the use of antiseptics and was a founding contributor to the germ theory of disease, who tragically took his life in the face of vehement opposition.

The connections that chemistry and science spawn are colourful and always intriguing.

As addicted as can be

I am reading the mind-blowing (no pun) book The Chemistry of Mind-Altering Drugs: History, Pharmacology and Cultural Context by Daniel Perrine. The book takes us through a whirlwind journey through the chemical structures, biological activity, social and historical significance, economics, neurowizardry, and politics associated with mind-altering drugs. It recounts fascinating tales of countless artists, scientists and common folk who experimented with these firecrackers and states verbatim their fantastic experiences and journeys into phantasmagoria. Caffeine, morphine, cocaine, heroin, marijuana, benzodiazapenes, LSD, barbiturates, amphetamines, ephedrine...they are all here. If you are a chemist or pharmacologist, you will find the details of the chemistry, synthesis, and interactions of these things with the brain fascinating, along with the other details. If a non-chemist, the other aspects should still be enough to keep you sunk in your chair on long evenings. After going through this stuff, all I can say is I cannot wait to lay my hands on some of these treats...

But one of the things that especially caught my interest was a discussion of "addiction scales" for various substances. Firstly, defining how addictive a substance is is a topic in its own right, and it's not easy to define "degree of addictiveness" if you will. But assuming that there are some reasonable criteria for defining addiction (ease of habit forming, difficulty of cutting one loose from the habit, probability of recurrence, withdrawal symptoms etc.), it comes somewhat as a surprise that it's nicotine which is number one on the list, the most addictive substance. Not cocaine, not heroin, but something legally used by millons everyday. A few more "mind-altering" surprises also await us:

1. As noted above, the most addictive substance is not controlled and is available over the counter
2. Cocaine and heroin, both highly controlled substances with criminal associations, are slightly more addictive than tea or coffee
3. Marijuana is consistently ranked less addictive than alcohol. So is mescaline from the peyote cactus.
4. Alcohol is the most addictive substance of all according to many criteria, and surely more so than marijuana

Now of course this does not mean that I might as well nonchalantly get a shot of heroin everyday instead of quaffing my giant mug of coffee. But these results tell us first and foremost how much the political restrictions and social perceptions on drug use are misguided and uninformed by rational study. Alcohol is many times more potent, habit forming, toxic, and fraught with undesirable and dangerous side-effects compared to marijuana, including in its propensity to cause road accidents. And yet pot is illegal while alcohol is a coveted legal commodity with high-culture connotations. Alcohol consumption also has so many more social problems associated with it precisely because it is also a social activity, and yet smoking marijuana even in a private setting is prohibited (or simply possessing it is prohibited...or whatever these crazy drug laws are...I can never remember).

What the government is doing by prohibiting marijuana is not saving lives or preventing crime. The fact that it has not forbidden alcohol clearly shows that that's not its primary goal. I seriously cannot understand what the primary goal in prohibiting marijuana is; it seems to be triggered by a mixture of pseudopious religious sentiments, anecdotal evidence, and knee-jerk social constraints (If someone consumes drugs, no matter what amount and what kind, he must be a completely wayward and purposeless subhuman by default). In any case, what the government is doing is to close up the drug market to competition, so that prices go up, transactions become closeted and riskier, and the business becomes riddled with dangers, crime lords and street gangs. If anything, many of these drug laws blatantly promote violence and crime. The production of these drugs can also not be curtailed. Amphetamines can be made from ephedrine (a common cough syrup constituent) by almost any amateur chemist. Kitchen chemistry can likewise be used for producing various grades of several other controlled substances.

The other point is that there are so many other things we encounter in life (violent video games? probably not) which are "addictive" and whose effects can be deemed as potentially harmful. Alcohol is probably the most egregiously neglected of these. What about addiction to car driving? Addiction to drinking coke? Addicting to sitting in roller coasters? Addiction to white-water rafting? Are these activities really free of danger to oneself and others? Obviously not. At the very least, consumption of mind-altering substances as a pleasure-providing activity similar to these other pursuits should be given due consideration in discussion. As the book also notes, food, chocolate, jogging, violence, God (surely so), exercise, sex and television also are addictive for certain individuals and come with the baggage of deleterious effects. For some reasons, we as a society have accepted these vices as legitimate and respectable. Clearly, though, in more than one sense, we are as addicted as anyone can be.

What the government needs to do is to have a realistic appraisal of the effects of various drugs. Naturally, alcohol is more dangerous than nicotine in terms of social behaviour, but nicotine can be much more dangerous in terms of personal and secondary health effects. Cocaine and heroin can be dangerous, but probably not as much as alcohol if used in tiny amounts privately. Acid trips caused by LSD likewise cause no harm if they consist of someone dancing in his or her room and writhing on the bed. And marijuana may be the most misunderstood brain-affecting substance ever, with every criterion of addiction for it ranking it on par with caffeine as the least addictive and dangerous substance. Legalize some of these drugs in a restricted manner and it may actually become much easier to keep track of who bought what and did what. Far from encouraging crime, it will likely restrict and surely make it easier to track and control it. Currently, most of the legislation on drugs has come less from rational debate and study and more from biases that have pushed the issue wholesale under the carpet and furiously pounded on it. After all, all these substances used to be consumed as medicines in diluted form by native tribes in Africa, Asia, and Central and South America. Clearly, they were wiser than we are (and in other contexts too)

Restricting many of these substances with a blank check is prosecuting what are famously called victimless crimes. But it also shows ignorance of sound scientific understanding of the effects, chemistry, production, and economics of drug use. Drug use, like religion, seems to be a topic on which the very notion of serious and reasoned debate is considered taboo. Government officials need to first have their own minds altered, before they pass legislation on these "mind-altering" substances.