IDENTIFYING POTENTIAL hENR INHIBITORS AGAINST PROSTATE CANCER EMPLOYING IN SILICO DRUG REPURPOSING APPROACH

Objective: This study employed an in silico drug repurposing strategy to identify potential human enoyl acyl carrier protein reductase (hENR) inhibitors. Methods: The co-crystallized ligand triclosan was used as a reference standard. Initially, FDA-approved drugs from the Drug Bank database were docked against the hENR and compounds with appreciable binding affinities with the protein were shortlisted. The binding energy calculations, ADME analysis, and induced-fit docking results of shortlisted compounds led to the identification of two top hits, DB07676 and DB11399, which were further subjected to molecular dynamics simulation. Results: Of 2,509 ligands docked via High Throughput Virtual Screening (HTVS), the top 250 were assessed with Standard Precision (SP) and the top 25 with Extra Precision (XP) mode. Thirteen compounds were selected based on interactions and XP scores, ranging from-15.245 to-10.031. Relative binding free energies of ligands DB07676 and DB11399 were-54.18 and-61.38 kcalmol-1, respectively. ADME analysis confirmed that both ligands followed Lipinski's Rule, though DB11399 had a high log P, which could be addressed by adding polar groups. Induced Fit scores for DB07676 and DB11399 were-10.592 and-11.220, respectively. Molecular Dynamics simulations confirmed superior stability of these complexes with RMSD ranging from 1.2 to 3.5 Å for the protein and 1.7 to 5.2 Å for the ligand with DB07676-protein complex and 1.4 to 3.0 Å for the protein and 1.1 to 5.8 Å for the ligand with DB11399-protein complex. Conclusion: Our final findings suggested that DB07676 and DB11399 could be potential lead compounds as hENR inhibitors.