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

Unlocking potential topoisomerase-II inhibitors: ligand-based drug design pipeline integrating pharmacophore mapping, virtual screening, molecular docking, and ADMET profiling

Abha Vyas, Paresh K. Patel, Saumya Patel, Nandan Dixit, and Sneha Sagar

Department of Pharmaceutical Chemistry, L.J. Institute of Pharmacy, L J University, Ahmedabad, India

E-mail: snehasagar291@gmail.com

Received: 22 September 2024  Accepted: 9 April 2025

Abstract:

Cancer, characterised by abnormal cell proliferation, is one of the most challenging diseases to provide effective and safe therapy. The aim of this study is to design inhibitors targeting DNA topoisomerase, a key enzyme responsible for regulating DNA topology during vital cellular processes like replication and transcription. By inhibiting this enzyme, we aim to develop novel therapeutic agents that can disrupt cancer cell proliferation and offer more effective treatment options. In course of our research to discover potent DNA topoisomerase inhibitors, ligand-based pharmacophore model was developed from 20 structurally diverse molecules which consist of four features including donor, acceptor, and aromatic regions. The generated features were used to design new acridine derivatives as potent DNA topoisomerase inhibitors. Molecular docking study was performed on the designed molecules (PDB ID: 6ZY6) in the XP (extra precision) of the Glide module. The docking results of the designed molecules have shown better results, and two compounds demonstrated favourable docking scores of −9.365 and −9.218 for molecule 1A23 and 1A29, respectively. Moreover, these compounds displayed favourable ADMET parameters. Molecular dynamics revealed that the top-ranked ligands exhibited enhanced ligand–protein binding stability. Based on these computational outcomes and binding affinity, these compounds will be used to design potent and bioactive lead molecules against cancer.

Graphical abstract

Keywords: Molecular Target Validation; Molecular Target Identification; Protein-Ligand Interactions; Small Molecules; Structure-Based Drug Design; DNA-binding proteins; DNA topoisomerase; Ligand-based pharmacophore; Molecular docking; ADMET

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-04103-7

Chemical Papers 79 (8) 5023–5038 (2025)