Effect of Substituents in Different Positions of Aminothiazole Hinge-Binding Scaffolds on Inhibitor–CDK2 Association Probed by Interaction Entropy Method

Abstract

Recently, CDK2 has been a promising target of drug development for the treatment of the myriad of various human diseases. Molecular dynamics (MD) simulations are integrated with an efficient interaction entropy method to probe the effect of substitutions at S1 and S2 positions of the aminothiazole hinge-binding scaffold (1-{4-amino-2-(alkyl(o-aryl)amino)thiazol-5-yl}arylmethanones) on binding of inhibitors to CDK2. The results suggest that a para-sulfonamide moiety or a meta-amino group of a phenyl ring introduced into S1 and S2 of the aminothiazole hinge-binding scaffold could not only improve the van der Waals interactions of inhibitors with CDK2, but also strengthen their electrostatic interactions. The hot interaction spots of inhibitors with residues of CDK2 were identified by performing scanning of hydrophobic contacts and hydrogen bond contacts of inhibitors with CDK2 on MD trajectories. The results show that the aminothiazole hinge-binding scaffold not only generates stable hydrophobic contacts wi...