Identification and comparison of plant-derived scaffolds as selective CDK5 inhibitors against standard molecules: Insights from umbrella sampling simulations

Abstract

The cyclin-dependent kinase 5 (CDK5) is an unusual member of the CDKs family due to its role in the central nervous system. The specific inhibition of cyclin-dependent kinase 5 (CDK5) is highly desirable in combating a wide range of conditions including, neurodegeneration, cancer, and diabetes. In this study, we elucidated the potential of in-house developed plant-derived semi-synthetic (AAB) analogues to act as ATP competitive inhibitors to selectively inhibit CDK5. We integrated high-end computational approaches including, explicit-solvent molecular dynamics (MD) simulations, steered MD simulations, and enhanced umbrella sampling simulations to rank and compare the AAB molecules with two selective CDK5 inhibitors (4a and Indolinone-A). Our results suggested the high affinity of AAB scaffolds (AAB-6 and AAB-8) to selectively interact with the active site of CDK5. Simultaneously, both these molecules showed unfavorable binding free energies for CDK2, manifesting selectivity for CDK5 over CDK2. Moreover, we demonstrated the possible unbinding pathways of the top AAB analogues from the catalytic pocket of CDK5 and compared them with the standard molecules. The present computational approach could also be used to target critical proteins involved in various diseases.