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

preprint
submitted on 01.09.2019 and posted on 04.09.2019 by Maria Khrenova, Anna M. Kulakova, Alexander Nemukhin

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.

Funding

Russian Science Foundation (project # 19-73-20032)

History

Email Address of Submitting Author

khrenova.maria@gmail.com

Institution

Lomonosov Moscow State University

Country

Russia

ORCID For Submitting Author

0000-0001-7117-3089

Declaration of Conflict of Interest

No conflict of interest

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