Unveiling structural components of dibenzofuran-based MMP-12 inhibitors: a comparative classification-dependent analysis with molecular docking-based virtual screening and molecular dynamics simulation

Jigme Sangay Dorjay Tamang; Suvankar Banerjee; Balaram Ghosh; Sandip Kumar Baidya; Tarun Jha; Nilanjan Adhikari

doi:10.1007/s40203-024-00296-z

Unveiling structural components of dibenzofuran-based MMP-12 inhibitors: a comparative classification-dependent analysis with molecular docking-based virtual screening and molecular dynamics simulation

In Silico Pharmacol. 2025 Jan 7;13(1):10. doi: 10.1007/s40203-024-00296-z. eCollection 2025.

Authors

Jigme Sangay Dorjay Tamang^#¹, Suvankar Banerjee^#¹, Balaram Ghosh², Sandip Kumar Baidya^{1

3}, Tarun Jha¹, Nilanjan Adhikari¹

Affiliations

¹ Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
² Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Shamirpet, Hyderabad, 500078 India.
³ School of Pharmacy, Sister Nivedita University, Action Area 1, Newtown, Kolkata, 700156 India.

^# Contributed equally.

PMID: 39780771
PMCID: PMC11704098 (available on 2026-01-07)
DOI: 10.1007/s40203-024-00296-z

Abstract

The implication of matrix metalloproteinase-12 (MMP-12) in various major disorders including cancer, COPD, cardiovascular disorders, and neurological diseases makes it a potential target for drug discovery. Contemplating the significance of MMP-12, a number of MMP-12 inhibitors were designed, synthesized and tested throughout the world but the non-selective nature of most of those molecules can lead to adverse drug interactions. In contradiction, the dibenzofuran (DBF) and dibenzothiophene (DBT) derivatives showed highly potent and selective MMP-12 inhibition. Therefore, to identify the prime molecular and structural attributes that are affecting the MMP-12 inhibitory activity, the linear discriminant analysis (LDA), Bayesian classification, recursive partitioning, and SARpy analysis were performed to extract the prime attributes of these DBFs and DBTs affecting MMP-12 inhibition. These studies suggested that substructures like isopropyl carboxylic acid, 5-methyl furan, 1,2,4-oxadiazole, and DBT moieties can impart moderate to high contribution for MMP-12 inhibition. Importantly, the outcomes of the current studies were also in agreement with our regression-based study performed earlier. Furthermore, the molecular docking-mediated virtual screening of DBT and DBF analogs of the ChEMBL database demonstrated the viability of other DBT and DBF analogs to become potential MMP-12-selective inhibitors. The molecular dynamics (MD) simulation study of hit molecules also showed the potential of the combination of phosphonic acid ZBG and DBF P1' substituent for effective anchoring/binding at the MMP-12 active site. Therefore, the findings may help in the discovery and designing of novel MMP-12 inhibitors that may be used for the treatment of various pathological diseases including cancer and COPD.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00296-z.

Keywords: Classification-based molecular modeling; MMP-12; Molecular docking; Molecular dynamics simulation; Virtual screening.

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.