Combined Virtual Screening, DFT Calculations and Molecular Dynamics Simulations to Discovery of Potent MMP-9 Inhibitors

Abstract

Background: Matrix metalloproteinase-9 (MMP-9) plays a crucial role in the development and progression of cancer. Therefore, identifying its inhibitors has enjoyed numerous attentions. In this report, a hybrid approach, including pharmacophore-based virtual screening, docking studies, and density functional theory (DFT) binding energy calculations followed by molecular dynamics simulations, was used to identify potential MMP-9 inhibitors. Methods: Pharmacophore modeling based on ARP101, as a known MMP-9 inhibitor, was performed and followed by virtual screening of ZINC database and docking studies to introduce a set of new ligands as candidates for potent inhibitors of MMP-9. The binding energies of MMP-9 and the selected ligands as well as ARP101, were estimated via the DFT energy calculations. Subsequently, molecular dynamics simulations were applied to evaluate and compare the behavior of ARP101 and the selected ligand in a dynamic environment. Results: (S,Z)-6-(((2,3-dihydro-1H-benzo[d]imidazol-2-yl)thio)methylene)-2-((4,6,7- trimethylquinazolin- 2-yl)amino)-1,4,5,6-tetrahydropyrimidin-4-ol, ZINC63611396, with the largest DFT binding energy, was selected as a proper potent MMP-9 inhibitor. Molecular dynamics simulations indicated that the new ligand was stable in the active site. Conclusion: The results of this study revealed that compared to the binding energies achieved from the docking studies, the binding energies obtained from the DFT calculations were more consistent with the intermolecular interactions. Also, the interaction between the Zinc ion and ligand, in particular the Zn2+-ligand distance, played a profound role in the quantity of DFT binding energies.