Biological and Medicinal Chemistry

Modeling the Interplay of Poor Inhibitor Binding and Efficient Formation of a Covalent Adduct upon the Interaction of ARS Compounds with KRASᴳ¹²ᶜ



We contribute to the emerging topic of development of the family of prospective covalent inhibitors of the “undraggable” KRAS protein. Recent experimental studies on the x-ray [Nature 2013; Cell, 2016], in vivo [Cancer Discov., 2016] and in vitro [Nat. Struct. Mol. Biol., 2018] kinetics reached the top of possible detalization of the process. Although many questions on the reaction mechanism still arise. Herein we utilize a set of supercomputer molecular modeling tools and our original strategy on kinetic analysis to evaluate the reaction mechanism of protein-inhibitor interactions to clarify them. Moreover we suggest original strategy to bridge the microscopic calculated parameters with the macroscopic observed ones and compare them.


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