A Molecular Mechanics‐Assisted Structure‐Based Virtual Screening Approach for Repurposing Clinically Approved Drugs as Putative MMP‐2 Binders

ABSTRACT

Matrix metalloproteinase‐2 (MMP‐2) contributes to pathological extracellular matrix (ECM) remodeling in cardiovascular, malignant, metabolic, and renal diseases. Its zinc‐dependent active site and hydrophobic S1′ specificity pocket make MMP‐2 an attractive yet challenging therapeutic target. This study used a molecular‐mechanics‐assisted structure‐based virtual screening strategy to identify approved drugs predicted to bind the MMP‐2 catalytic domain for subsequent evaluation as potential inhibitors. A library of 7,173 stereoisomers representing 4,574 purchasable approved drugs was docked into the active site and evaluated using ligand‐efficiency metrics, predicted docking scores, and molecular‐mechanics calculations. Compounds with predicted Zn ²⁺ coordination and favorable S1′‐pocket interactions were prioritized, particularly those bearing weak‐to‐moderate zinc‐binding groups (ZBGs). The screen identified orally bioavailable candidates from several therapeutic classes, including antifolates, cysteinyl‐leukotriene receptor 1 antagonists, and peroxisome proliferator‐activated receptor agonists. These findings suggest that some approved drugs possess ZBGs and elongated P1′ substituents compatible with non‐hydroxamate binding to MMP‐2. This approach may facilitate rapid, cost‐effective prioritization of putative MMP‐2 binders for diseases involving pathological ECM turnover while benefiting from existing human pharmacological and safety data. Biochemical validation and cross‐MMP selectivity testing remain necessary.