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

Mechanistic exploration of dog bone-shaped tacrine analogues as telomerase inhibitors via 3D-QSAR, MD simulations, and energy landscape analysis

Rajdeep Dey, Nandan Dixit, Saumya Patel, and Hardik Bhatt

Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, India

E-mail: hardikbhatt23@hotmail.com

Received: 14 July 2025  Accepted: 2 December 2025

Abstract:

Telomerase is a pivotal target for oncological therapeutics. This study leverages cutting-edge computational methodologies to design and optimise tacrine analogues as telomerase inhibitors. Using the Schrödinger suite, we employed the PHASE module for 3D-QSAR modeling, Glide for molecular docking, and DESMOND for molecular dynamics (MD) simulations. Two series of dog-bone-shaped derivatives, namely N-benzoyl-N-(1,2,3,4-tetrahydroacridin-9-yl)benzamides and N-(1,2,3,4-tetrahydroacridin-9-yl)benzamides, were rationally designed to improve binding affinity and target specificity. Molecular docking studies revealed binding energies of − 10.45 and − 9.86 kcal/mol for the lead compounds HB_01 and HB_02, surpassing the performance of standard inhibitors BIBR1532 and BRACO-19. MD simulations validated the stability of protein–ligand complexes, with root mean square deviation values consistently below 3 Å. Binding free energy analyses (MM/GBSA) highlighted thermodynamic favorability, with ΔG_bind values of − 71.189 kcal/mol for HB_01 and − 71.7 kcal/mol for HB_02. Principal component analysis and free energy landscape (FEL) analyses further corroborated the dynamic stability and conformational compactness of the complexes, showcasing the synergistic application of these computational techniques. By providing a comprehensive workflow from 3D-QSAR to FEL analysis, this work establishes a scalable framework for telomerase inhibitor development. Future studies will expand on these insights through experimental validation, leveraging computational precision for advanced anticancer therapeutics.

Keywords: hTERT inhibitors; Telomerase; QSAR; Molecular dynamics; Tacrine; MM/GBSA; Anticancer; Computational drug design

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-04578-4

Chemical Papers 80 (3) 3165–3187 (2026)