Modulating structural dynamics of dual drugs for CDK4 complex addressing prostate cancer

Abstract

Multiple drug therapies have been proposed to inhibit dysregulated activation of cyclin-dependent kinases (CDK) 4/6, resulting in primary or secondary resistance or partial deactivation. Owing to the presence of drug repurposing and drug combination therapies, the current study targeted p27-CDK4/cyclin D1 complex to investigate nine different experimentally verified drug combinations targeting the central binding groove (CBG) and ATP binding site. Our findings reveal top drug combinations that impart stability to dimer in active conformation are: ShetA2-Palbociclib, ShetA2-Abemaciclib (IC50, 2 nM), and Letrozole-Ribociclib (IC50, 11 nM). Impact of dual inhibition on structure dynamics categorically demonstrates the role of catalytic amino acids (Asp341 and Ala166) that forges interactions with aromatic rings and chemical scaffolds particularly pyrido-pyrimidine substructures efficaciously uphold an active conformation. Furthermore, the role of p27 linker is emphasized and validated that modulates compact domain organization and confers enhanced structure stability thus acting as molecular effectors of dual drugs binding in solution. Additionally, local conformational changes, hydrophobic microenvironment around CBG, and polar ATP site underpin the significance of aromatic rings in ligands that serve as targets for prostate cancer. Conclusively, the ADMET properties of combination drugs, the structural dynamics of each inhibitor in its respective binding site, and molecular determinants for enhanced binding affinities provide summarized data on dual inhibition therapy that can significantly aid in designing accurate dual inhibitors.