Molecular dynamics study on inhibition mechanism of CDK-2 and GSK-3β by CHEMBL272026 molecule

Abstract

CDK-2 and GSK-3β are kinases that exhibit a high level of similarity in the context of amino acid sequence and structural properties of the active site. Both considered enzymes fulfill an important role in the regulation of cell cycle, and disorders in their proper functioning can trigger many serious diseases, even cancer. Identification of potential inhibitors with selective properties is not a trivial task. The potential group of compounds with such properties comprises indirubin derivatives and their analogs. The ligand molecule was docked to two enzymes, namely CDK-2 and GSK-3β, with the use of AutoDock Vina package. The stability of obtained complexes was evaluated with the use of molecular dynamics simulations realized with the use of AMBER11. Both complexes obtained during docking stage are stabilized by network of hydrogen bonds containing similar number of interactions. However, the time evolution of these systems shows significant discrepancies in terms of stability of these interactions and conformational flexibility of ligand molecule. Differences observed for dynamics and structural properties also confirm the values of binding affinity for examined systems. CHEMBL272026 molecule exhibits binding properties toward both considered kinases. However, binding affinity values and examined interactions denoted for both complexes show significant discrepancies in stability of both systems, indicating the higher inhibiting properties toward CDK-2 active site. The discovery of inhibitors with selective potential is an important task, and investigating the mechanism of kinases inhibition may reveal factors responsible for the increase in selective properties what can contribute to the development of new groups of compounds.