Synthetic chemistry is for roundheads, medicinal chemistry should be for cavaliers

The last blog post on the subject of Roundheads and Cavaliers prompted me to reflect about how good I think the analogy is and whether it is useful. It eventually got me wondering about another, related subject that I have struggled to find the words to describe. This is the divergence between the mindsets of two sub-disciplines of chemistry: synthetic and medicinal chemistry. Although it may no longer show, my PhD training was in synthetic chemistry. One of the things that I enjoyed most during that period was the retrosynthesis challenge that would be set for the group. We would work in small groups to try and concoct a convincing synthetic approach to various fiendish molecules. These would then be presented to the rest of the group who would provide robust criticism of the proposed schemes – it was a terrifying undertaking for a first year graduate student but a satisfying thrill by the time I was finished. The great challenge was to have a synthesis that would get past the immense cumulative knowledge of a world-leading bunch of synthetic chemists. The whole session hinged on the transferability of reactions from one context to another. Those who knew the most detail from the literature would always “win” – and what is more, this was (almost always) because they could reasonably say that they knew what would work and what would not. Hence, their proposed syntheses could be better informed than everybody else’s and they could provide more informed critique of the other syntheses.

This is an appalling preparation for medicinal chemistry.

It has frequently shocked me to hear medicinal chemists pontificating about what will and will not work. It has too often felt like a delusion. Actually, that’s not quite right. In terms of stacking the odds in your favour, it is a pretty good idea to say that everything will not work. This makes medicinal chemistry ideal territory for self-satisfied Roundheads. But how unhelpful, how uninspiring. In an environment in which little is understood definitively, we require persistent sorts who can take the knocks of things not working as hoped and can pick themselves up and do it all again. A corrosive presence that will decrease the prospects of success is the one who can only tell you why they think something will not work or worse, the “told you so” sorts who don’t even make testable predictions. I fear that the puritanical roundheads of synthetic chemistry are all too often in this category. Is this really the best training for the random bittersweetness of drug discovery? What sort of training can we provide that will bring more joie de vivre to the undertaking, where do we find cavaliers and how do we train them?

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Synthetic chemistry is for roundheads, medicinal chemistry should be for cavaliers

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