Computational exploration of allosteric inhibitors targeting CDK4/CDK6 proteins: a promising approach for multi-target drug development

Cyclin-dependent kinases (CDKs) play a pivotal role in orchestrating the intricate regulation of the cell cycle, a fundamental process governing cell growth and division. In particular, CDK4 and CDK6 are critical for the transition from the G1 phase to the S phase, where Deoxyribonucleic acid (DNA) replication occurs, and their dysregulation is linked to various diseases, notably cancer. While ATP-binding site inhibitors for CDKs are well-documented, this study focuses on uncovering allosteric inhibitors, providing a fresh perspective on CDK inhibition. Computational techniques were employed in this investigation, utilizing Molecular Operating Environment (MOE) for virtual screening of a drug-like compound library. Moreover, the stability of the most promising binding inhibitors was assessed through Molecular Dynamics (MD) simulations and MMPBSA/MMGBSA analyses. The outcome reveals that three inhibitors (C1, C2, and C3) exhibited the strongest binding affinity for CDK4/CDK6, as corroborated by docking and simulation analyses. The computed binding energies ranged from −6.1 to −7.6 kcal/mol, underscoring the potency of these allosteric inhibitors. Notably, this study identifies key residues (PHE31, HIS95, HIS100, VAL101, ASP102, ASP104, and THR107) that play pivotal roles in mediating inhibitor binding within the allosteric sites. Among the findings, the C1–CDK4 complex and C2–CDK6 complex emerge as particularly promising inhibitors, exhibiting high binding energies, favorable interaction patterns, and sustained presence within the active site. This study contributes significantly to the pursuit of multi-target drugs against CDK4/CDK6 proteins, with potential implications for the development of innovative therapies across various disorders, including cancer and other cell cycle-related conditions.