PMID- 34384998 OWN - NLM STAT- MEDLINE DCOM- 20211103 LR - 20211103 IS - 1476-928X (Electronic) IS - 1476-9271 (Linking) VI - 94 DP - 2021 Oct TI - Cell-based assays and molecular simulation reveal that the anti-cancer harmine is a specific matrix metalloproteinase-3 (MMP-3) inhibitor. PG - 107556 LID - S1476-9271(21)00123-7 [pii] LID - 10.1016/j.compbiolchem.2021.107556 [doi] AB - The biological activities of harmine have been a much clearer picture in recent years, which include anti-tumor, anti-inflammation and cytotoxic properties. Numerous in vitro and in vivo animal models have confirmed its activities, but its mode of action remains a relative unsolved issue. We therefore investigated harmine for its effects on MMP-3 and the molecular interaction was also simulated. The human glioma cancer cell line, U-87 MG cells, was subjected to different concentrations (1-10 muM) of harmine for 24 h. Methylthiazol tetrazolium (MTT) test, half maximal inhibitory concentration (IC50), western blot analysis, enzyme-linked immunosorbent assay and molecular docking through BIOVIA DiscoveryStudio were performed. These results showed that although harmine stimulation in vitro has very little or no effects on MMP-3 expression by U-87 MG cells, the treatment of harmine decreases MMP-3 activity in a dose dependent manner. It was further calculated that 7.9 muM is the IC50 towards MMP-3. Using a molecular dynamic simulation approach, we identified the N2, methyl of C1 and benzene ring of harmine interact with Zn(2+) (2.4 A), His205 (2.4 A) and His211 (2.4 A) as well as Val163 (2.7 A) at the active site of MMP-3, respectively, and thus conferred a striking specific binding advantage. Taken altogether, the present study evidences that harmine acts as an MMP-3 inhibitor specially targeting the enzymatic active site and possibly efficiently ameliorates MMP-3-driven malignant and inflammatory diseases. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Chin, Li-Te AU - Chin LT AD - Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi City, 60004, Taiwan, ROC; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City, 11400, Taiwan, ROC. FAU - Liu, Ke-Wei AU - Liu KW AD - Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi City, 60004, Taiwan, ROC. FAU - Chen, Yi-Han AU - Chen YH AD - Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi City, 60004, Taiwan, ROC. FAU - Hsu, Shu-Ching AU - Hsu SC AD - Synergy Biomedical Corp., Hsinchu City, 30054, Taiwan, ROC. FAU - Huang, Lin AU - Huang L AD - Synergy Biomedical Corp., Hsinchu City, 30054, Taiwan, ROC. Electronic address: x0915369728@gmail.com. LA - eng PT - Journal Article DEP - 20210806 PL - England TA - Comput Biol Chem JT - Computational biology and chemistry JID - 101157394 RN - 0 (Antineoplastic Agents) RN - 0 (Enzyme Inhibitors) RN - 4FHH5G48T7 (Harmine) RN - EC 3.4.24.17 (MMP3 protein, human) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM MH - Antineoplastic Agents/chemistry/isolation & purification/*pharmacology MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Drug Screening Assays, Antitumor MH - Enzyme Inhibitors/chemistry/isolation & purification/*pharmacology MH - Harmine/chemistry/isolation & purification/*pharmacology MH - Humans MH - Matrix Metalloproteinase 3/*metabolism MH - *Molecular Docking Simulation MH - Tumor Cells, Cultured OTO - NOTNLM OT - Harmine OT - Matrix metalloproteinase-3 (MMP-3) OT - Molecular docking EDAT- 2021/08/14 06:00 MHDA- 2021/11/04 06:00 CRDT- 2021/08/13 06:02 PHST- 2021/04/07 00:00 [received] PHST- 2021/07/20 00:00 [revised] PHST- 2021/07/29 00:00 [accepted] PHST- 2021/08/14 06:00 [pubmed] PHST- 2021/11/04 06:00 [medline] PHST- 2021/08/13 06:02 [entrez] AID - S1476-9271(21)00123-7 [pii] AID - 10.1016/j.compbiolchem.2021.107556 [doi] PST - ppublish SO - Comput Biol Chem. 2021 Oct;94:107556. doi: 10.1016/j.compbiolchem.2021.107556. Epub 2021 Aug 6.