TOWARD ENRICHED VHTS FOR CDK2 INHIBITORS: MOLECULAR DYNAMICS, PHARMACOPHORE MODELLING, AND DOCKING

Abstract

Cyclin-Dependent Kinases-2 (CDK2) are members of the serine/threonine protein kinases family. They play an important role in the regulation events of the eukaryotic cell division cycle, especially during the G1 to S phase transition. Experimental evidence indicates that excessive expression of CDK2s should cause abnormal cell cycle regulation. Therefore, since a long time, CDK2s have been considered potential therapeutic targets for cancer therapy. In this work, we collected one-hundred and forty-nine complexes of inhibitors bound in the CDK2-ATP pocket submitting to short MD simulations (10ns) and free energy calculation by means of MM-GBSA. The calculate ∆G values have been compared with experimental data (Ki, Kd, and IC50). Information collected on short MD simulations of protein-ligand complexes has been used to perform molecular modeling approaches that incorporates flexibility into structure-based pharmacophore modeling (Common Hits Approach, CHA,1 and Molecular dYnamics SHAred PharmacophorE, MYSHAPE2 approach) and constraints docking, to enrich the hits list of virtual screening. Short simulations proved to be exhaustive to examine the crucial ligand-protein interactions within the complexes.