Arylamide as Potential Selective Inhibitor for Matrix Metalloproteinase 9 (MMP9): Design, Synthesis, Biological Evaluation, and Molecular Modeling
| Autor: | Jeffry Julianus, Maywan Hariono, Ervan S. Nugroho, Ratna Dwi Ramadani, Riris Istighfari Jenie, Muhammad Yusuf, Reynaldo Tiara, Lailatul Qodria, Rina Fajri Nuwarda, Rollando Rollando, Benedictus W. Jati, Sangga P. Dewa, Yohanes K. Wisnumurti, Belal O. Al-Najjar, Kevin C. Putra, Habibah A. Wahab |
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| Rok vydání: | 2019 |
| Předmět: |
Molecular model
General Chemical Engineering Library and Information Sciences MMP9 Molecular Dynamics Simulation 01 natural sciences Molecular Docking Simulation Catalytic Domain 0103 physical sciences Chlorocebus aethiops Animals Humans Protease Inhibitors Cytotoxicity Vero Cells chemistry.chemical_classification 010304 chemical physics Chemistry Cell growth Cellular Assay General Chemistry Combinatorial chemistry Amides 0104 chemical sciences Computer Science Applications body regions 010404 medicinal & biomolecular chemistry Förster resonance energy transfer Enzyme Matrix Metalloproteinase 9 Drug Design |
| Zdroj: | Journal of chemical information and modeling. 60(1) |
| ISSN: | 1549-960X |
| Popis: | Previous studies have reported that compounds bearing an arylamide linked to a heterocyclic planar ring have successfully inhibited the hemopexin-like domain (PEX9) of matrix metalloproteinase 9 (MMP9). PEX9 has been suggested to be more selectively targeted than MMP9's catalytic domain in a degrading extracellular matrix under some pathologic conditions, especially in cancer. In this study, we aim to synthesize and evaluate 10 arylamide compounds as MMP9 inhibitors through an enzymatic assay as well as a cellular assay. The mechanism of inhibition for the most active compounds was investigated via molecular dynamics simulation (MD). Molecular docking was performed using AutoDock4.0 with PEX9 as the protein model to predict the binding of the designed compounds. The synthesis was carried out by reacting aniline derivatives with 3-bromopropanoyl chloride using pyridine as the catalyst at room temperature. The MMP9 assay was conducted using the FRET-based MMP9 kits protocol and gelatin zymography assay. The cytotoxicity assay was done using the MTT method, and the MD simulation was performed using AMBER16. Assay on MMP9 demonstrated activities of three compounds (2, 7, and 9) with more than 50% inhibition. Further inhibition on MMP9 expressed by 4T1 showed that two compounds (7 and 9) inhibited its gelatinolytic activity more than 50%. The cytotoxicity assay against 4T1 cells results in the inhibition of the cell growth with an EC50 of 125 μM and 132 μM for 7 and 9, respectively. The MD simulation explained a stable interaction of 7 and 9 in PEX9 at 100 ns with a free energy of binding of -8.03 kcal/mol and -6.41 kcal/mol, respectively. Arylamides have potential effects as selective MMP9 inhibitors in inhibiting breast cancer cell progression. |
| Databáze: | OpenAIRE |
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