Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro
The development of small-molecule drugs targeting growth factors for cancer therapy remains a significant challenge, with only limited successful cases. We attempted to identify hepatocyte growth factor (HGF) inhibitors as novel anti-cancer small-molecule drugs. To identify compounds that bind to th...
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2025-04-01
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| author | Ko Suzuki Keitaro Inoue Ryota Namiguchi Seiya Morita Suzuho Hayakawa Mikuri Yokota Katsuya Sakai Kunio Matsumoto Shunsuke Aoki |
| author_facet | Ko Suzuki Keitaro Inoue Ryota Namiguchi Seiya Morita Suzuho Hayakawa Mikuri Yokota Katsuya Sakai Kunio Matsumoto Shunsuke Aoki |
| author_sort | Ko Suzuki |
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| description | The development of small-molecule drugs targeting growth factors for cancer therapy remains a significant challenge, with only limited successful cases. We attempted to identify hepatocyte growth factor (HGF) inhibitors as novel anti-cancer small-molecule drugs. To identify compounds that bind to the β-chain of HGF and inhibit signaling through HGF and its receptor Met interaction, we performed a hierarchical in silico drug screen using a three-dimensional compound structure library (Chembridge, 154,118 compounds). We experimentally tested whether 10 compounds selected as candidates for novel anticancer agents exhibit inhibition of HGF activity. Compounds <b>6</b> and <b>7</b> potently inhibited Met phosphorylation in the human EHEMES-1 cell line, with IC<sub>50</sub> values of 20.4 and 11.9 μM, respectively. Molecular dynamics simulations of the Compound <b>6</b>/<b>7</b>–HGF β-chain complex structures suggest that Compounds <b>6</b> and <b>7</b> stably bind to the interface pocket of the HGF β-chain. MM-PBSA, MM-GBSA, and FMO analyses identified crucial amino acid residues for inhibition against the HGF β-chain. By interfering with the HGF/Met interaction, these compounds may attenuate downstream signaling pathways involved in cancer cell proliferation and metastasis. Further optimization and comprehensive evaluations are necessary to advance these compounds toward clinical application in cancer therapy. |
| format | Article |
| id | doaj-art-188f87bec6344683bd70f833da2bebe5 |
| institution | OA Journals |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-04-01 |
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| series | Molecules |
| spelling | doaj-art-188f87bec6344683bd70f833da2bebe52025-08-20T02:28:41ZengMDPI AGMolecules1420-30492025-04-01308180110.3390/molecules30081801Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In VitroKo Suzuki0Keitaro Inoue1Ryota Namiguchi2Seiya Morita3Suzuho Hayakawa4Mikuri Yokota5Katsuya Sakai6Kunio Matsumoto7Shunsuke Aoki8Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDivision of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, JapanWPI-Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanThe development of small-molecule drugs targeting growth factors for cancer therapy remains a significant challenge, with only limited successful cases. We attempted to identify hepatocyte growth factor (HGF) inhibitors as novel anti-cancer small-molecule drugs. To identify compounds that bind to the β-chain of HGF and inhibit signaling through HGF and its receptor Met interaction, we performed a hierarchical in silico drug screen using a three-dimensional compound structure library (Chembridge, 154,118 compounds). We experimentally tested whether 10 compounds selected as candidates for novel anticancer agents exhibit inhibition of HGF activity. Compounds <b>6</b> and <b>7</b> potently inhibited Met phosphorylation in the human EHEMES-1 cell line, with IC<sub>50</sub> values of 20.4 and 11.9 μM, respectively. Molecular dynamics simulations of the Compound <b>6</b>/<b>7</b>–HGF β-chain complex structures suggest that Compounds <b>6</b> and <b>7</b> stably bind to the interface pocket of the HGF β-chain. MM-PBSA, MM-GBSA, and FMO analyses identified crucial amino acid residues for inhibition against the HGF β-chain. By interfering with the HGF/Met interaction, these compounds may attenuate downstream signaling pathways involved in cancer cell proliferation and metastasis. Further optimization and comprehensive evaluations are necessary to advance these compounds toward clinical application in cancer therapy.https://www.mdpi.com/1420-3049/30/8/1801hepatocyte growth factor (HGF)SBDSmolecular dockingMDSfragment molecular orbitalMet |
| spellingShingle | Ko Suzuki Keitaro Inoue Ryota Namiguchi Seiya Morita Suzuho Hayakawa Mikuri Yokota Katsuya Sakai Kunio Matsumoto Shunsuke Aoki Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro Molecules hepatocyte growth factor (HGF) SBDS molecular docking MDS fragment molecular orbital Met |
| title | Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro |
| title_full | Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro |
| title_fullStr | Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro |
| title_full_unstemmed | Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro |
| title_short | Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro |
| title_sort | identification of novel compounds that bind to the hgf β chain in silico verification by molecular mechanics and quantum mechanics and validation of their hgf inhibitory activity in vitro |
| topic | hepatocyte growth factor (HGF) SBDS molecular docking MDS fragment molecular orbital Met |
| url | https://www.mdpi.com/1420-3049/30/8/1801 |
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