Structure-Based Virtual Screening and ADMET Evaluation of Inhibitors Targeting the Androgen Receptor for Prostate Cancer Therapy
DOI:
https://doi.org/10.62382/sfnnm155Keywords:
Androgen Receptor, Prostate Cancer, Bicalutamide, Molecular Docking, ADMET, Virtual Screening, PS AnaloguesAbstract
Purpose: Persistent activation of the androgen receptor (AR) remains a major driver of prostate cancer progression, particularly in castration-resistant forms, necessitating the development of novel inhibitors with improved efficacy and pharmacokinetic profiles. This study aimed to identify potential AR inhibitors using a structure-based virtual screening approach. Methods: The AR ligand-binding domain (PDB ID: 1Z95) was employed for molecular docking of a designed library of Prostate Specific (PS) analogues using MVD. Drug-likeness was evaluated based on Lipinski’s Rule of Five, and top-ranked compounds were further assessed through in silico absorption, distribution, metabolism and toxicity (ADMET) profiling to predict pharmacokinetic and toxicity properties. Results: Several PS analogues demonstrated stronger predicted binding affinities than the reference drug bicalutamide (-131.19 kcal/mol), with PS-073 showing the highest MolDock score (-155.84 kcal/mol). Key interactions with residues such as Met745, Gln738, and Leu704 contributed to enhanced binding profiles. Compounds including PS-049, PS-057, and PS-067 exhibited favorable predicted absorption and distribution characteristics, although some analogues showed potential mutagenicity or hepatotoxicity alerts. Conclusion: The identified PS analogues represent promising scaffolds for androgen receptor inhibition, demonstrating improved binding interactions and acceptable predicted pharmacokinetic profiles compared to bicalutamide. However, further experimental validation and structural optimization are required to confirm their therapeutic potential.
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