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

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 with conserved residues V18 and L134, but also form stable hydrogen bond contacts with conserved residues E81 and L83. Among the current substitutions, a para-sulfonamide moiety or a meta-amino group of a phenyl ring at S1 and S2 of the aminothiazole hinge-binding scaffold displays potential to improve the binding ability of inhibitors to CDK2. We expect that this study can contribute significant guidance to design potent inhibitors targeting CDK2.