Identification of Novel Natural Product Inhibitors against Matrix Metalloproteinase 9 Using Quantum Mechanical Fragment Molecular Orbital-Based Virtual Screening Methods |
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Authors: | Hocheol Lim Hansol Hong Seonik Hwang Song Ja Kim Sung Yum Seo Kyoung Tai No |
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Affiliation: | 1.The Interdisciplinary Graduate Program in Integrative Biotechnology & Translational Medicine, Yonsei University, Incheon 21983, Korea; (H.L.); (H.H.);2.Bioinformatics and Molecular Design Research Center (BMDRC), Incheon 21983, Korea;3.Department of Biotechnology, Yonsei University, Seoul 03722, Korea;4.Department of Biological Science, Kongju National University, Kongju 32588, Korea; (S.J.K.); (S.Y.S.);5.Baobab AiBIO Co., Ltd., Incheon 21983, Korea |
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Abstract: | Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases involved in multiple cellular processes. Among the MMP isoforms, MMP-9 regulates cancer invasion, rheumatoid arthritis, and osteoarthritis by degrading extracellular matrix proteins present in the tumor microenvironment and cartilage and promoting angiogenesis. Here, we identified two potent natural product inhibitors of the non-catalytic hemopexin domain of MMP-9 using a novel quantum mechanical fragment molecular orbital (FMO)-based virtual screening workflow. The workflow integrates qualitative pharmacophore modeling, quantitative binding affinity prediction, and a raw material search of natural product inhibitors with the BMDMS-NP library. In binding affinity prediction, we made a scoring function with the FMO method and applied the function to two protein targets (acetylcholinesterase and fibroblast growth factor 1 receptor) from DUD-E benchmark sets. In the two targets, the FMO method outperformed the Glide docking score and MM/PBSA methods. By applying this workflow to MMP-9, we proposed two potent natural product inhibitors (laetanine 9 and genkwanin 10) that interact with hotspot residues of the hemopexin domain of MMP-9. Laetanine 9 and genkwanin 10 bind to MMP-9 with a dissociation constant (KD) of 21.6 and 0.614 μM, respectively. Overall, we present laetanine 9 and genkwanin 10 for MMP-9 and demonstrate that the novel FMO-based workflow with a quantum mechanical approach is promising to discover potent natural product inhibitors of MMP-9, satisfying the pharmacophore model and good binding affinity. |
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Keywords: | matrix metalloproteinase 9 fragment molecular orbital quantum chemistry virtual screening structure-based drug design laetanine genkwanin |
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