Decoding structural fingerprints of matrix metalloproteinase-9 inhibitors targeting the medium-sized S1' pocket

Matrix metalloproteinase-9 (MMP-9), a zinc-dependent endopeptidase integral to extracellular matrix (ECM) remodeling, plays a pivotal role in physiological processes such as tissue repair and angiogenesis. A comprehensive cheminformatics study, including chemical space network analysis, scaffold diversity analysis, and fragment-based modelling, was employed to investigate the structural and physicochemical determinants of MMP-9 inhibitory activity, aiming to facilitate the rational design of promising inhibitors. The Bayesian classification, recursive partitioning studies extract key structural features driving MMP-9 inhibition include- (a) aryl hydrophobic scaffolds (e.g., 4-phenoxyphenyl) that fit well into the S1' pocket, consistent with Bayesian fingerprints G1, G4, and G5, (b) triazole rings, highlighted by G2, which may take part to enhance MMP-9 inhibitory activity (e.g., C1919 with IC₅₀ = 0.07 nM), (c) arylthioethyl substituents emphasized by G8, likely projecting into the S1' pocket to improve binding interactions. Further, molecular docking and DFT calculations were performed, indicating a tetrahedral zinc coordination complex during binding. 200 ns molecular dynamics (MD) simulations were performed for selected inhibitors (C1790 and C1910) to evaluate binding modes and complex stability. Collectively, this integrative workflow provided robust predictive models and mechanistic insights, supporting the design of novel MMP-9 inhibitors with improved efficacy.