Docking and database screening identify manidipine as a potential modulator of matrix metalloproteinase-7 in chronic...

Matrix metalloproteinases (MMPs) are a critical family of proteolytic enzymes responsible for extracellular matrix (ECM) remodeling and degradation. Among them, MMP7 has emerged as a key regulator in the pathogenesis of kidney diseases, exerting a more pronounced influence than other MMPs. In this study, we aimed to identify a potential bioactive drug targeting MMP7 and investigate its molecular mechanisms in chronic kidney disease (CKD) using both in vitro and in vivo models. A virtual drug screening was employed to discover candidate compounds with high affinity to the MMP7 target protein using the DrugBank database. The biological effects of the identified drug were subsequently validated through in vitro experiments in kidney cells and in vivo studies using a CKD mouse model. Manidipine reduced MMP7 enzymatic activity by a fluorogenic peptide substrate. Manidipine functionally enhanced autophagy while suppressing NLRP3/NLRP6 inflammasome activation in kidney cells in vitro and in vivo. Additionally, manidipine significantly downregulated the expression of fibrosis-related proteins, leading to a reduction in renal fibrosis. In experimental CKD models, manidipine treatment improved renal function and mitigated structural kidney damage. Manidipine attenuated the progression of CKD by regulating MMP7 activity, autophagy, inflammasomes and fibrosis in kidney tissues. These findings reveal a novel renoprotective mechanism of manidipine, suggesting its potential as a therapeutic agent for attenuating CKD progression.