Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics Simulations
The development of effective inhibitors targeting the Kirsten rat sarcoma viral proto-oncogene (KRAS<sup>G12D</sup>) mutation, a prevalent oncogenic driver in cancer, represents a significant unmet need in precision medicine. In this study, an integrated computational approach combining...
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| Format: | Article |
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MDPI AG
2024-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/6/1229 |
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| author | Zhenya Du Gao Tu Yaguo Gong Xiangzheng Fu Qibiao Wu Guankui Long |
| author_facet | Zhenya Du Gao Tu Yaguo Gong Xiangzheng Fu Qibiao Wu Guankui Long |
| author_sort | Zhenya Du |
| collection | DOAJ |
| description | The development of effective inhibitors targeting the Kirsten rat sarcoma viral proto-oncogene (KRAS<sup>G12D</sup>) mutation, a prevalent oncogenic driver in cancer, represents a significant unmet need in precision medicine. In this study, an integrated computational approach combining structure-based virtual screening and molecular dynamics simulation was employed to identify novel noncovalent inhibitors targeting the KRAS<sup>G12D</sup> variant. Through virtual screening of over 1.7 million diverse compounds, potential lead compounds with high binding affinity and specificity were identified using molecular docking and scoring techniques. Subsequently, 200 ns molecular dynamics simulations provided critical insights into the dynamic behavior, stability, and conformational changes of the inhibitor-KRAS<sup>G12D</sup> complexes, facilitating the selection of lead compounds with robust binding profiles. Additionally, in silico absorption, distribution, metabolism, excretion (ADME) profiling, and toxicity predictions were applied to prioritize the lead compounds for further experimental validation. The discovered noncovalent KRAS<sup>G12D</sup> inhibitors exhibit promises as potential candidates for targeted therapy against KRAS<sup>G12D</sup>-driven cancers. This comprehensive computational framework not only expedites the discovery of novel KRAS<sup>G12D</sup> inhibitors but also provides valuable insights for the development of precision treatments tailored to this oncogenic mutation. |
| first_indexed | 2024-04-24T17:57:51Z |
| format | Article |
| id | doaj.art-0335af92a77647459f2493b39bc49576 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-24T17:57:51Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-0335af92a77647459f2493b39bc495762024-03-27T13:56:47ZengMDPI AGMolecules1420-30492024-03-01296122910.3390/molecules29061229Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics SimulationsZhenya Du0Gao Tu1Yaguo Gong2Xiangzheng Fu3Qibiao Wu4Guankui Long5State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao 999078, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao 999078, ChinaSchool of Materials Science and Engineering, National Institute for Advanced Materials, Renewable Energy Conversion and Storage Center (RECAST), Nankai University, Tianjin 300350, ChinaThe development of effective inhibitors targeting the Kirsten rat sarcoma viral proto-oncogene (KRAS<sup>G12D</sup>) mutation, a prevalent oncogenic driver in cancer, represents a significant unmet need in precision medicine. In this study, an integrated computational approach combining structure-based virtual screening and molecular dynamics simulation was employed to identify novel noncovalent inhibitors targeting the KRAS<sup>G12D</sup> variant. Through virtual screening of over 1.7 million diverse compounds, potential lead compounds with high binding affinity and specificity were identified using molecular docking and scoring techniques. Subsequently, 200 ns molecular dynamics simulations provided critical insights into the dynamic behavior, stability, and conformational changes of the inhibitor-KRAS<sup>G12D</sup> complexes, facilitating the selection of lead compounds with robust binding profiles. Additionally, in silico absorption, distribution, metabolism, excretion (ADME) profiling, and toxicity predictions were applied to prioritize the lead compounds for further experimental validation. The discovered noncovalent KRAS<sup>G12D</sup> inhibitors exhibit promises as potential candidates for targeted therapy against KRAS<sup>G12D</sup>-driven cancers. This comprehensive computational framework not only expedites the discovery of novel KRAS<sup>G12D</sup> inhibitors but also provides valuable insights for the development of precision treatments tailored to this oncogenic mutation.https://www.mdpi.com/1420-3049/29/6/1229KRAS<sup>G12D</sup>noncovalent inhibitorvirtual screeningmolecular dynamics |
| spellingShingle | Zhenya Du Gao Tu Yaguo Gong Xiangzheng Fu Qibiao Wu Guankui Long Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics Simulations Molecules KRAS<sup>G12D</sup> noncovalent inhibitor virtual screening molecular dynamics |
| title | Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics Simulations |
| title_full | Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics Simulations |
| title_fullStr | Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics Simulations |
| title_full_unstemmed | Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics Simulations |
| title_short | Discovery of Novel Noncovalent KRAS G12D Inhibitors through Structure-Based Virtual Screening and Molecular Dynamics Simulations |
| title_sort | discovery of novel noncovalent kras g12d inhibitors through structure based virtual screening and molecular dynamics simulations |
| topic | KRAS<sup>G12D</sup> noncovalent inhibitor virtual screening molecular dynamics |
| url | https://www.mdpi.com/1420-3049/29/6/1229 |
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