Structure-based Drug Design and Pharmacokinetic Profiling of Novel Heterocyclic Androgen Receptor Inhibitors for Prostate Cancer Treatment
Vanktesh Kumar, Shivank Sharma, Saminesh Kumar, Pankaj WadhwaIntroduction/Background:
Prostate cancer is one of the most prevalent malignancies and the second leading cause of cancer-related death in men after cardiovascular diseases. Currently available therapies, such as bicalutamide, suffer from limitations, including off-target effects and resistance, highlighting the urgent need for novel androgen receptor (AR) inhibitors with improved binding affinity, pharmacokinetic properties, enhanced efficacy, and reduced adverse effects.
Materials and Methods:
On the basis of its structural similarity to bicalutamide, virtual screening of the PubChem database yielded 100 heterocyclic compounds. These molecules were subjected to molecular docking against the androgen receptor (PDB ID: 1Z95) via AutoDock Vina to evaluate binding interactions. The docking accuracy was validated using root-mean-square deviation (RMSD) analysis and comparison with the co-crystallized ligand. The top 10 ligands with the highest binding affinities were further assessed for their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles via pkCSM and the Toxicity Estimation Software Tool (TEST).
Results:
Docking studies identified HARIc-001 as the most potent AR inhibitor, with a binding energy of −10.30 kcal/mol, which was greater than that of bicalutamide (−9.00 kcal/mol). Key hydrogen bonding interactions with Lys808 and Asn756 contributed to the increased binding affinity of this protein. ADMET analysis revealed that HARIc-001 had superior predicted intestinal absorption (91.5%) compared to bicalutamide (81.3%), along with favorable solubility, metabolic stability, and toxicity profiles, supporting its potential oral bioavailability and safety.
Discussion:
The enhanced binding affinity of HARIc-001 relative to bicalutamide may be attributed to stronger hydrogen bonding and optimized interactions within the AR ligand-binding pocket. The improved predicted pharmacokinetic properties further suggest that rational modification of heterocyclic scaffolds can yield AR antagonists with superior drug-like profiles. These findings support the utility of structure-based virtual screening combined with ADMET prediction as an effective strategy for early-stage lead identification in prostate cancer drug discovery.
Conclusion:
This study highlights HARIc-001 as a promising novel AR antagonist with improved binding affinity and favorable pharmacokinetic characteristics compared with bicalutamide. The results provide a foundation for subsequent in vitro and in vivo validation, structural optimization, and preclinical development of next-generation AR inhibitors for prostate cancer therapy.