Repository of Research and Investigative Information

Repository of Research and Investigative Information

دانشگاه علوم پزشکی و خدمات بهداشتی درمانی زنجان

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

(2019) Combined Virtual Screening, DFT Calculations and Molecular Dynamics Simulations to Discovery of Potent MMP-9 Inhibitors. Letters in Drug Design & Discovery. pp. 892-903. ISSN 1570-1808, 1875-628X

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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-benzodimidazol-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 Zn-2(+)-ligand distance, played a profound role in the quantity of DFT binding energies.

Item Type: Article
Keywords: Drug discovery, matrix metalloproteinase-9 inhibitor, virtual screening, DFT energy calculation, molecular dynamics simulations. density functional theory.
Divisions: Education Vice-Chancellor Department > Faculty of Pharmacy > گروه شیمی دارویی
Page Range: pp. 892-903
Journal or Publication Title: Letters in Drug Design & Discovery
Abstract and Indexing: ISI, Scopus
Quartile : Q4
Volume: 16
Number: 8
Publisher: Bentham
Identification Number:
ISSN: 1570-1808, 1875-628X
ISBN: 1570-1808
Depositing User: خانم فائزه مظفری

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