ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Computational screening and prediction of some compounds from national chemical database as BRD4-BD1 inhibitors through molecular docking and dynamics simulations

Abhishek Wahi, Imran A. Khan, Nancy Tripathi, and Priti Jain

Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), Govt. of NCT of Delhi, New Delhi, India

E-mail: pmj.dpsru@gmail.com

Received: 30 July 2024  Accepted: 18 August 2025

Abstract:

Prostate cancer (PC) is the second most diagnosed cancer and a significant cause of mortality among men globally. Castration-resistant prostate cancer (CRPC) poses a challenge due to its resistance to conventional androgen deprivation therapy (ADT). Targeting the bromodomain and extraterminal domain (BET) family proteins, particularly BRD4, has shown potential in treating CRPC. This study involves molecular docking of 54 molecules against the acetyl–lysine binding site of BRD4's first bromodomain (BD1) using PDB structure 5Y8Z. A pharmacophore model was generated and validated, followed by screening the NCI database. Concurrently, a 3D QSAR model predicted activity. Virtual screening, MM-GBSA analysis, and ADMET prediction were performed, with many discovered compounds showing improved G-scores (− 9.495 to − 8.002 kCal∙mol⁻¹) toward BRD4-BD1. Five promising compounds—NSC321246, NSC16725, NSC10021, NSC131751, and NSC40091—were subjected to MD simulations followed by MM-PBSA calculations. NSC40091 emerged as the most promising candidate, exhibiting high binding energy, moderate activity, and appropriate ADME characteristics. Despite NSC321246's highest Glide Gscore of − 9.495, it had the lowest ADME results. MD simulations confirmed NSC40091's stability, flexibility, and favorable hydrogen bonding, highlighting its potential as a therapeutic agent for CRPC. Further, experimental validation is necessary to develop selective BET inhibitors for CRPC treatment.

Keywords: Prostate cancer; Bromodomain; 3D QSAR; Pharmacophore modeling; Virtual screening; Molecular dynamics

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-04321-z

Chemical Papers 79 (12) 8395–8415 (2025)