Scaffold-based Screening and Molecular Dynamics Simulation Study to Identify Two Structurally Related Phenolic Compounds as Potent MMP1 Inhibitors

Abstract

Background: Matrix metalloproteinase 1 are zinc-dependent endopeptidases responsible for the controlled breakdown of the extracellular matrix resulting in the maintenance of homeostasis. Dysregulation of MMP1 leads to the progression of various pathological conditions like cancer, rheumatoid arthritis, cardiovascular disease, skin damage and fibrotic disorder. Thus, MMP1 inhibition is the potential drug target of many synthetic MMP1 inhibitors but lack of substrate specificity hinders their clinical applicability. Hence, inhibitors from natural products have gained widespread attention.

Objective: The present study attempts screening of novel MMP1 inhibitors from the ZINC database based on experimentally reported natural inhibitors of MMP1 as a scaffold.

Methods: Molecular docking study was performed with 19 experimentally reported natural inhibitors spanning across nine different classes followed by virtual screening using the selected compounds. The selected compounds were subjected to molecular dynamics simulation.

Results: Twenty compounds were screened with a cut-off of -9.0 kcal/mol of predicted free energy of binding, which further converged to 6 hits after docking studies. After comparing the docking result of 6 screened hits, two best compounds were selected. ZINC02436922 had the best interaction with six hydrogen bond formation to a relatively confined region in the S1'site of MMP1 and -10.01 kcal/mol of predicted free energy of binding. ZINC03075557 was the secondbest compound with -9.57 kcal/mol predicted binding free energy. Molecular dynamics simulation of ZINC02436922 and ZINC03075557 corroborates docking study.

Conclusion: This study indicated phenolic compounds ZINC02436922 and ZINC03075557 as potential MMP1 inhibitors.

Keywords: MMP1; molecular docking; molecular dynamics simulation; natural inhibitor; phenolics; virtual screening.