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Big Trouble in Little Synthetic Organic Chemistry?

Sunday, October 2, 2016 21:04
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Michael Rafferty who teaches in the Department of Medicinal Chemistry at the University of Kansas has a thought-provoking article in the Journal of Medicinal Chemistry in which he questions whether it’s time to reinvent the model for training academic scientists in graduate programs to better equip them for the complexity and rigor of modern drug discovery. His target is the cadre of synthetic organic chemists who for decades have functioned as the indispensable backbone of the pharmaceutical industry. The title of the article – “No Denying It: Medicinal Chemistry Training Is In Big Trouble” – should be self-explanatory, in case anyone is wondering where exactly the author’s sentiments lie on the topic.

Even today when you say that someone is a “medicinal chemist” it usually means someone who is trained as a synthetic organic chemist, who either goes into the lab and makes molecules himself or herself or who directs other people to do the same. Rafferty is asking whether the decades-old standard of recruitment into medicinal chemistry groups in the pharmaceutical industry – sound training in synthetic organic chemistry – might have to be revised.

Rafferty’s basic point is that the kind of wisdom needed to find hits, advance them into lead compounds and finally into drug candidates does not really benefit from having a background in pure synthetic organic chemistry: it’s much more about SAR analysis and understanding pharmacological properties. As he points out, the pharmaceutical industry has of course realized and maintained that all that wisdom can be learnt on the job. But Rafferty is not sure, and part of his skepticism comes from two revealing studies that basically showed two things: first, that even experienced medicinal chemists do not agree when picking good leads, and second, that most medicinal chemists even now don’t really take optimum properties into account when designing compounds. The problem with lead picking is thus not synthesis, it’s an ability to parse a complex landscape of multiple properties. Multiparameter optimization is still a beast whose footprints are rarely found among the thinking of medicinal chemists.

I think in general he’s right. Advances in pharmacology, toxicology, computational chemistry and other fields over the past few decades have made it possible to both calculate as well as use property-based information in early stages of drug discovery. The article focuses on lipophilicity as one parameter which really should be considered on a regular basis but which isn’t a lot of time. The problem is that a lot of synthesis has turned into a machine for cranking out molecules, so drug discovery scientists end up making molecules because they can be easily made. It’s a theme that I and others have written about previously: making molecules is no longer the rate determining step in drug discovery: design is the important paradigm. One of the reasons is that CROs in China and India can now often make molecules as easily as in-house synthetic chemists. In one sense what the article is saying is because these CROs can now pick up the slack, chemists can use the time to more productively think about property-based optimization.

Now while I think it’s cogent to include as much property information as possible in early drug discovery, it’s worth noting that some of this information is dubious and some is valuable; the problem is that often it’s hard to say which information would be dubious and which would be valuable. One of the reasons medicinal chemists disagree on compound selection is because gut instincts and experience can sometimes overrule what may seem like cogent limits on properties like lipophilicity. Nonetheless, having medicinal chemists who are tuned by default to thinking about properties would be a good idea. 

The second caveat I would apply to approaches like this is to not discount the value of a classical synthetic organic chemistry education. As has been amply demonstrated, making a complex molecule over a long period of time is more about handling setbacks, persisting with grit and developing the kind of character that can handle repeated failures than about making the molecule per se. And god knows we need all these qualities in drug discovery, a field which is literally a glutton for attrition and failure. In addition, even today there are molecules which often stump the best efforts of standard synthetic routes. Thus, it’s always a good idea to have a core group of accomplished synthetic chemists in any program. In one sense the argument is really about degree, it’s about what the size of this core should be, and the article argues that maybe it should be smaller than what has been traditionally thought.

Rafferty’s main prescription is that graduate programs training chemists for drug discovery should now focus less on synthesis and more on multiparameter optimization and on other disciplines which can be used to think about properties upfront. The industry should do likewise in deemphasizing training of synthetic organic chemistry and emphasizing broader training in medicinal chemistry during recruitment. When I was in graduate school I was fortunate to study under a world-class medicinal chemist. Not only did his group teach students to think about properties at a relatively early stage, but more in line with what this article says, he also created a very good drug discovery course which gave students a solid flavor of the process and emphasized the contributions of other disciplines like pharmacology, formulation, metabolic studies and molecular modeling. Rafferty is encouraging more graduate programs to include such courses, and I definitely agree with him on this. The second prescription he has is to create more industry-academic partnerships in which industry contributes personnel, scholarships and funding to expose students to actual drug discovery and not just synthesis. A scheme like this has been in place in Europe for some time now.

Wikipedia seems to have caught up with the times when it defines medicinal chemistry as a discipline which 

“In its most common practice —focusing on small organic molecules—encompasses synthetic organic chemistry and aspects of natural products and computational chemistry in close combination with chemical biologyenzymology and structural biology, together aiming at the discovery and development of new therapeutic agents. Practically speaking, it involves chemical aspects of identification, and then systematic, thorough synthetic alteration of new chemical entities to make them suitable for therapeutic use. It includes synthetic and computational aspects of the study of existing drugs and agents in development in relation to their bioactivities (biological activities and properties), i.e., understanding their structure-activity relationships (SAR).”

Perhaps academia and industry can embrace this definition more fully.

Image: Amriglobal

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