Authors
Kritika Sharma, N D Yash, Mansi Dangi, Maitree Kadamb, Aparna Shrivastava, J Senthil Kumaran, Sakshi Yadav, Monika Jain, Amit Kumar Singh, Jayaraman Muthukumaran
Published in
Journal of molecular modeling. Volume 32. Issue 10. Sep 28, 2026. Epub Sep 28, 2026.
Abstract
Dysregulation of apoptosis mediated by antiapoptotic Bcl-2 family proteins contributes significantly to cancer progression and treatment resistance. Although the BH3 mimetic venetoclax has demonstrated remarkable clinical efficacy, the emergence of resistance-associated mechanisms has created a need for alternative Bcl-2-targeting scaffolds. Benzopyran derivatives, including 4H-chromene and chromone derivatives, represent a structurally diverse class of compounds with reported anticancer and apoptosis-modulating activities; however, their interaction landscape with Bcl-2 remains insufficiently explored. In the present study, a curated library of 356 benzopyran family compounds was investigated against Bcl-2 to identify potential lead candidates. Three compounds, PM28524659, PM31145889, and PM34262894, exhibited favorable binding characteristics relative to the reference chromene-derived Bcl-2 inhibitor HA14-1. Binding mode analysis indicated occupancy of the BH3-binding groove, with interactions involving ASP49, ARG53, and TYR148 residues. Molecular similarity, scaffold, and pharmacophore analyses revealed preservation of key target recognition features despite low overall structural similarity to HA14-1. Based on their physicochemical, pharmacokinetic, and molecular descriptor profiles, PM28524659 and PM31145889 were selected for further investigation through long-timescale molecular dynamics simulations. Both complexes remained stable throughout the 500-ns MD simulation period and maintained favorable interactions with the binding pocket while preserving the overall structural integrity of Bcl-2 protein. Although the identified compounds exhibited lower predicted binding affinity than venetoclax, their favorable ligand efficiency, relatively simple molecular architecture, and scope for structural optimization support their further evaluation as Bcl-2-targeting scaffolds for apoptosis-directed anticancer drug discovery.
A dataset comprising 356 curated benzopyran family compounds was subjected to virtual screening against Bcl-2 (PDB ID: 6O0K) using AutoDock Vina. Protein-ligand interactions were analyzed using Discovery Studio Visualizer and PyMOL. Molecular similarity, scaffold, and pharmacophore analyses were performed using two-dimensional and three-dimensional descriptor-based approaches. Drug-likeness, physicochemical properties, pharmacokinetic parameters, and toxicity profiles were assessed using SwissADME, ProTox-3, and related cheminformatics tools. The selected protein-ligand complexes were further investigated by 500-ns molecular dynamics simulations using GROMACS 2025.3 and the CHARMM36 force field in an explicit solvent environment employing the CHARMM-modified TIP3P water model. Trajectory analyses included root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), intermolecular hydrogen bond analysis, principal component analysis (PCA), and MM/PBSA-based binding free energy analysis to characterize structural stability, residue-level flexibility, compactness, protein-ligand interactions, dominant collective essential motions, and binding affinity. The trajectory-derived parameters were further subjected to descriptive statistical and distributional analyses using Python-based tools, including Pandas, NumPy, Matplotlib, and Seaborn, with correlation and cross-correlation analyses used to examine parameter relationships and variability across the simulated systems.
PMID:
42804025
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.
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