Drug Repurposing of Statins for MMP-2 Modulation: Insights from Docking and Structural Dynamics

Abstract

MMP-2 is a vital endopeptidase implicated in extracellular matrix remodeling, tumor invasion, and metastasis in ovarian cancer; its targeting thus represents a promising therapeutic approach. Statins are widely prescribed HMG-CoA reductase inhibitors which have shown pleiotropic anticancer effects, while carboplatin remains one of the standard chemotherapeutic agents in ovarian cancer therapy. This paper evaluates the potential of selected statins as allosteric inhibitors of MMP-2 through an in silico drug repurposing strategy. The three-dimensional structure of the hemopexin-like domain of MMP-2 was retrieved from the Protein Data Bank (PDB ID: 1RTG) and refined using GalaxyRefine. Secondary structure and physicochemical properties were analyzed by PSIPRED and ProtParam, respectively. Molecular docking studies were performed using Schrödinger Glide to assess binding affinities of eight statins and carboplatin with MMP-2. Further characterizations of the molecular interactions were done through hydrogen bonding, hydrophobic contacts, and Pi–alkyl interactions. Protein–ligand complex stability and dynamics were assessed using NMA along with ENM via iMODS. Among the statins, atorvastatin showed the strongest binding affinity (ΔG = −7.9 kcal/mol) with MMP-2, outperforming carboplatin (ΔG = −6.6 kcal/mol). The docking analysis revealed critical interaction of atorvastatin with GLY215, TRP212, and HIS42. Stability and flexibility of the atorvastatin–MMP-2 complex were observed through NMA and ENM. The obtained results provide evidence of an allosteric inhibition mechanism. Other statins showed moderate binding affinities, while carboplatin was primarily found to interact via its conventional DNA-targeting mode. This study suggests that atorvastatin may act as an allosteric inhibitor of MMP-2, hereby presenting a novel repurposing opportunity for ovarian cancer therapy. Predictions based on computational analysis indicate favourable binding as well as structural stabilization of the MMP-2 regulatory domain; further in vitro and in vivo validation is required. Used in combination with standard chemotherapeutics like carboplatin, it may improve therapeutic efficacy with minimum off-target effects.