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

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.