Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives
More people are being diagnosed with resistant breast cancer, increasing the urgency of developing new effective treatments. Several lines of evidence suggest that blocking the kinase activity of VEGFR-2 reduces angiogenesis and slows tumor growth. In this study, we developed novel VEGFR-2 inhibitor...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1288652/full |
| _version_ | 1797490203058765824 |
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| author | Soukayna Baammi Soukayna Baammi Achraf El Allali Rachid Daoud |
| author_facet | Soukayna Baammi Soukayna Baammi Achraf El Allali Rachid Daoud |
| author_sort | Soukayna Baammi |
| collection | DOAJ |
| description | More people are being diagnosed with resistant breast cancer, increasing the urgency of developing new effective treatments. Several lines of evidence suggest that blocking the kinase activity of VEGFR-2 reduces angiogenesis and slows tumor growth. In this study, we developed novel VEGFR-2 inhibitors based on the triazolopyrazine template by using comparative molecular field analysis (CoMFA) and molecular similarity indices (CoMSIA) models for 3D-QSAR analysis of 23 triazolopyrazine-based compounds against breast cancer cell lines (MCF -7). Both CoMFA (Q2 = 0.575; R2 = 0.936, Rpred2 = 0.956) and CoMSIA/SE (Q2 = 0.575; R2 = 0.936, Rpred2 = 0.847) results demonstrate the robustness and stability of the constructed model. Six novel compounds with potent inhibitory activity were carefully designed, and screening of ADMET properties revealed their good oral bioavailability and ability to diffuse through various biological barriers. When compared with the most active molecule in the data set and with Foretinib (breast cancer drug), molecular docking revealed that the six designed compounds had strengthened affinity (−8.9 to −10 kcal/mol) to VEGFR-2. Molecular Dynamics Simulations and MMPBSA calculations were applied to the selected compound T01 with the highest predicted inhibitory activity, confirming its stability in the active pocket of VEGFR-2 over 100 ns. The present results provided the basis for the chemical synthesis of new compounds with improved inhibitory properties against the breast cancer cell line (MCF -7). |
| first_indexed | 2024-03-10T00:28:38Z |
| format | Article |
| id | doaj.art-7090036dd81f48b1bcd57d890c98d790 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-03-10T00:28:38Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-7090036dd81f48b1bcd57d890c98d7902023-11-23T15:28:51ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-11-011010.3389/fmolb.2023.12886521288652Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivativesSoukayna Baammi0Soukayna Baammi1Achraf El Allali2Rachid Daoud3Chemical and Biochemical Sciences-Green Processing Engineering, Mohammed VI Polytechnic University, Ben Guerir, MoroccoBioinformatics Laboratory, College of Computing, Mohammed VI Polytechnic University, Ben Guerir, MoroccoBioinformatics Laboratory, College of Computing, Mohammed VI Polytechnic University, Ben Guerir, MoroccoChemical and Biochemical Sciences-Green Processing Engineering, Mohammed VI Polytechnic University, Ben Guerir, MoroccoMore people are being diagnosed with resistant breast cancer, increasing the urgency of developing new effective treatments. Several lines of evidence suggest that blocking the kinase activity of VEGFR-2 reduces angiogenesis and slows tumor growth. In this study, we developed novel VEGFR-2 inhibitors based on the triazolopyrazine template by using comparative molecular field analysis (CoMFA) and molecular similarity indices (CoMSIA) models for 3D-QSAR analysis of 23 triazolopyrazine-based compounds against breast cancer cell lines (MCF -7). Both CoMFA (Q2 = 0.575; R2 = 0.936, Rpred2 = 0.956) and CoMSIA/SE (Q2 = 0.575; R2 = 0.936, Rpred2 = 0.847) results demonstrate the robustness and stability of the constructed model. Six novel compounds with potent inhibitory activity were carefully designed, and screening of ADMET properties revealed their good oral bioavailability and ability to diffuse through various biological barriers. When compared with the most active molecule in the data set and with Foretinib (breast cancer drug), molecular docking revealed that the six designed compounds had strengthened affinity (−8.9 to −10 kcal/mol) to VEGFR-2. Molecular Dynamics Simulations and MMPBSA calculations were applied to the selected compound T01 with the highest predicted inhibitory activity, confirming its stability in the active pocket of VEGFR-2 over 100 ns. The present results provided the basis for the chemical synthesis of new compounds with improved inhibitory properties against the breast cancer cell line (MCF -7).https://www.frontiersin.org/articles/10.3389/fmolb.2023.1288652/fullbreast cancerVEGFR-23D-QSARADMETtriazolopyrazinemolecular docking |
| spellingShingle | Soukayna Baammi Soukayna Baammi Achraf El Allali Rachid Daoud Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives Frontiers in Molecular Biosciences breast cancer VEGFR-2 3D-QSAR ADMET triazolopyrazine molecular docking |
| title | Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives |
| title_full | Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives |
| title_fullStr | Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives |
| title_full_unstemmed | Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives |
| title_short | Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives |
| title_sort | potent vegfr 2 inhibitors for resistant breast cancer a comprehensive 3d qsar admet molecular docking and mmpbsa calculation on triazolopyrazine derivatives |
| topic | breast cancer VEGFR-2 3D-QSAR ADMET triazolopyrazine molecular docking |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1288652/full |
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