Tweetorial: How Med Chemists Think
4 August 2021
A look inside the nonlinear thinking in a medicinal chemist’s head. Scary.
Also, GIFs remain in full effect.
🧵I mentioned in passing last week that I wasn't going to get started on "Why are you getting PK on that compound? It isn't potent!" But now the idea's stuck in my head, so I guess I will. (Many papers on this kind of thing; one below.) 1/
nature.com/articles/nrd37…
Questions like this put to medicinal chemists are deeply at odds with how medicinal chemists think and problem solve. Non-chemists throw around the phrase "structure activity relationship" (SAR) loosely, and often think primarily of potency against the target. 2/
A definition of SAR that I like and have used in presentations is "how a measured property of a molecule varies as a function of its molecular architecture". The measured property CAN be (and often is) target potency, but that's a quite limited view of medicinal chemistry. 3/
Indeed, potency is often one of the easier problems to solve, especially w/ structural enablement. It's all of the other problems that keep us up at night. I'll take the series with good PK baked in from the start over the one with better potency any day. 5/
In this big Venn diagram, our job is to find the intersection of as many circles as possible. Thus the chemist is constantly seeking to balance all of these various SARs to deliver a drug candidate. This almost always entails making trade-offs in some areas to prop up others. 6/
So, when a chemist puts an inactive/less active compound into PK, they know before they do it that this molecule won't be the drug candidate. But they *are* testing a PK SAR hypothesis. That CH3 or F that reduced activity may also drop clearance from sky-high to manageable. 7/
It provides information that allows us to start fitting together the jigsaw in ways that maybe aren't immediately obvious. It can't be captured in a rigid, linear "screening cascade" document that's all too common in industry. But that doesn't make it any less essential to do. 8/
