Structure-Based Virtual Screening and Molecular Dynamics Simulation of FDA-Approved Drugs Targeting Mutant Androgen Receptor (8FGY) in Prostate Cancer

Most men are patients of a high-prevalent malignancy called prostate carcinoma which has a castration-resistant state termed CRPC that causes therapy problems due to mutations of androgen receptor (AR). This study aims to identify FDA-approved drugs that can bind and inhibit the clinically relevant mutant AR ligand-binding domain (PDB ID: 8FGY) through a structure-based virtual screening approach and molecular dynamic simulation. 3D mutant structure of AR was refined and validated before docking it to a curated library of drug-approved compounds using DrugRep webserver. The top-ranked candidates resulted from binding affinity and included Pregnenolone, Fluoxymesterone that were subjected to flexibility and stability investigation of protein-ligand complexes using Normal Mode Analysis (NMA). Results showed a couple of structurally high-affinity binders that are proving worthy for a future repurposing against anatomically resistant variants of prostate carcinoma. These findings advocate the importance of computer-based repurposing approaches in speeding the process of drug discovery for cancers resistant to treatment.