Marine-Derived Compounds for CDK5 Inhibition in Cancer: Integrating Multi-Stage Virtual Screening, MM/GBSA Analysis and Molecular Dynamics Investigations

Abstract

Cyclin-dependent kinase 5 (CDK5) plays a crucial role in various biological processes, including immune response, insulin secretion regulation, apoptosis, DNA (deoxyribonucleic acid) damage response, epithelial−mesenchymal transition (EMT), cell migration and invasion, angiogenesis, and myogenesis. Overactivation of CDK5 is associated with the initiation and progression of cancer. Inhibiting CDK5 has shown potential in suppressing cancer development. Despite advancements in CDK5-targeted inhibitor research, the range of compounds available for clinical and preclinical trials remains limited. The marine environment has emerged as a prolific source of diverse natural products with noteworthy biological activities, including anti-cancer properties. In this study, we screened a library of 47,450 marine natural compounds from the comprehensive marine natural product database (CMNPD) to assess their binding affinity with CDK5. Marine compounds demonstrating superior binding affinity compared to a reference compound were identified through high-throughput virtual screening, standard precision and extra-precision Glide docking modes. Refinement of the selected molecules involved evaluating molecular mechanics–generalized born surface area (MM/GBSA) free binding energy. The three most promising compounds, (excoecariphenol B, excoecariphenol A, and zyzzyanone B), along with the reference, exhibiting favorable binding characteristics were chosen for molecular dynamics (MD) simulations for 200 nanoseconds. These compounds demonstrated interaction stability with the target during MD simulations. The marine compounds identified in this study hold potential as effective CDK5 inhibitors and warrant subsequent experimental validation.

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“…The three PDB structures were submitted to the protein preparation wizard of Schrodinger's Maestro 12.8 software package [ 43 ]. In subsequent, the proteins were preprocessed, this entails the addition of any missing hydrogens, the assignment of the bond orders in each amino acid, the deletion of any heteroatom or solvent molecule within 5 Å, the optimization of hydrogen bonds, and the creation of zero-ordered bonds to the metals [ 44 ]. In the follower step, the missing loops and/or chains were checked and added using Maestro's Prime module.…”