Subtle structural effects in modern drug discovery

Thanks to Dr. Yusheng Xiong, I had a very informative visit to Merck in Kenilworth (New Jersey) this past Friday. The location of this site is very close to Rahway, which used to be Merck’s primary medicinal chemistry center. Since the acquisition of Schering-Plough several years ago, Kenilworth has been steadily turning into the main discovery hub for Merck.

While I can’t describe the proprietary details I learned during this trip, I can make several general statements that define the overall visit. When compared to the days past, there is clearly a new approach to drug discovery at Merck. This company used to be very much a small molecule-driven operation. It is now more about “whichever modality fits the target in question”. This is the main reason why there is so much interest in macrocycles, which was one of the topics covered in my lecture.

My second point is more scientific. Throughout the day, I had several discussions that involved some stereoelectronic arguments. While I cannot talk about them, I think I can mention a paper that just came out in J. Med. Chem. It describes the role of divalent sulfur in the structures of therapeutic agents and provides an excellent demonstration of intramolecular oxygen-sulfur interactions. Take a close look at the two structures below. There is no way (in my view) of guessing which one of these two extremely similar compounds is more effective in inhibiting VEGF. Interestingly, one of them is potent, whereas the other is completely inactive. People are just beginning to fully appreciate the involvement of sigma hole-driven interactions and, in the example below, conformational stabilization is evidenced in the shorter through-space O-S distance in the active molecule compared to the “dud”.


4 thoughts on “Subtle structural effects in modern drug discovery

    • Hahaha! Well – while some details might be confidential, I do convey general scientific flavor by referring to published work which, by the way, is from BMS in this case. Gotta respect the CDA agreements, but let people know that there are cool papers I discuss with folks!

  1. there are two main reasons for loving macrocycles, apart form the usual entropic argument about constraining the active conformation: 1) They tend to improve cell permeability (that’s why Nature puts them so prominently into all kinds of toxic molecules) 2) They improve patentability. A new macrocyclic ring (new means differing by just one heteroatom from what is the prior art) = a new composition of matter. Patent busting has never been easier

  2. I think this is partially correct. It is very optimistic to assume that macrocycles are cell-permeable. The ones made of amino acids are unfortunately not so hot in this capacity. Those that are permeable tend to be exceptions (although we are trying to address that!). I totally agree about patentability.

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