Allosteric Modulation of Dysregulated MMP-1 in OSCC: Structure Based Computational-Experimental Drug Discovery

Overview

Oral squamous cell carcinoma (OSCC), a major subtype of head and neck squamous cell carcinoma (HNSC), is characterized by aggressive extracellular matrix (ECM) degradation driven in part by overexpression of matrix metalloproteinase-1 (MMP-1). RNA-seq analysis of Cancer Genome Atlas HNSC dataset using GEPIA2 revealed significant MMP-1 overexpression (log₂FC = 6.266), corresponding to approximately 76-fold higher expression in tumor tissue. Current MMP-1 inhibitors primarily target the conserved catalytic zinc-binding site, often resulting in poor selectivity and off-target toxicity across the MMP family. This study investigated whether the hemopexin (HPX) domain, a regulatory domain involved in substrate recognition, could serve as a selective allosteric target.Structural analysis of human MMP-1 (PDB ID: 2CLT) using DoGSiteScorer identified a highly druggable HPX-domain pocket. Approximately 14,000 compounds from PubChem were screened through a hybrid computational pipeline including chemical filtering, molecular docking, selectivity cross-docking, ADME/toxicity screening, and 90 ns molecular dynamics simulations. This process yielded YC-1 as the top candidate with strong binding affinity(-9.5 kcal/mol) and drug-like properties. Molecular dynamics analysis demonstrated that YC-1 induced a stable conformational state distinct from apo MMP-1 and exhibited structural changes/fluctuations consistent with long-range allosteric modulation.In vitro enzyme kinetics assays performed in triplicate, with NNGH as a positive control, showed that YC-1 produced moderate inhibition of MMP-1 activity without zinc chelation, indicating a distinct type of inhibition. These results highlight the potential of targeting the HPX domain for selective MMP-1 inhibition, showcasing a combined computational–experimental approach developing precision drugs in OSCC.

Competition history

• CSEF 2026 Medicine & Physiology (Senior Division) · Entry S-15-29

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