In recent years, targeted covalent inhibitor design has gained widespread interest in drug discovery programs as a way to improve selectivity and potency. In such a design, an electrophilic warhead is added to a reversible inhibitor to covalently engage a nucleophilic residue in the target protein. Thus, it is desirable to develop a computational tool to predict and rationalize highly nucleophilic sites. In this talk, I will discuss our recent efforts in developing and applying the GPU-accelerated continuous constant pH molecular dynamics tool to retro- and prospectively predict reactive cysteine and lysine locations in a large number of kinases, including 14 MAP kinases and all kinases that possess a so-called Ncap cysteine. Time permitted, i will also present our most result findings of reactive residues in KRAS proteins.

Accurate and fast predictions of reactive cysteine and lysine locations for targeted covalent drug design

ACS Spring 2022

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