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Large-Scale Prediction of the ARS Family Inhibitors of the Oncogenic KRASG12C Mutant

  • Anna M. Kulakova
  • Anna V. PopinakoEmail author
  • Maria G. KhrenovaEmail author
Conference paper
  • 9 Downloads
Part of the Lecture Notes in Computer Science book series (LNCS, volume 11958)

Abstract

The KRAS protein is a molecular switch that activates cellular processes, like cell growth and differentiation. The G12C point mutation of the KRAS is found in various cancer cells. It results in the accretion of the GTP-bound active form thus accelerating downstream signalling pathways. Recently ARS family of compounds was suggested as selective covalent inhibitors of the KRASG12C. The most prospective ARS-853 has IC\(_{50}\) = 1.6 \(\upmu \)M that is too large for the medicinal applications. We demonstrate that calculated dissociation constants K\(_\mathrm{d}\) are proportional to the experimental IC\(_{50}\) values and can be utilized as a measure of the inhibitor potency. Using molecular modeling tools we suggest a set of novel compounds with the predicted IC\(_{50}\) values more than an order of magnitude lower than that of the ARS-853.

Keywords

KRASG12C Oncogenic mutation Covalent inhibitor Molecular docking ARS. 

Notes

Acknowledgments

M.G. Khrenova and A.M. Kulakova acknowledge financial support from the RFBR according to the research project No 18-29-13006. The research is carried out using the equipment of the shared research facilities of HPC computing resources at Lomonosov Moscow State University.

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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of ChemistryLomonosov Moscow State UniversityMoscowRussia
  2. 2.Bach Institute of Biochemistry, Federeal Research Center “Fundamentals of Biotechnology” of the Russian Academy of SciencesMoscowRussia

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