Discovery of novel SOS1 inhibitors using machine learning
文献类型：期刊论文
| 作者 | Duo, Lihui7; Chen, Yi3,5 ; Liu, Qiupei5,7; Ma, Zhangyi7; Farjudian, Amin1; Ho, Wan Yong4; Low, Sze Shin7; Ren, Jianfeng7; Hirst, Jonathan D.6; Xie, Hua2,3,5
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| 刊名 | RSC MEDICINAL CHEMISTRY
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| 出版日期 | 2024-04-24 |
| 卷号 | 15期号:4页码:1392-1403 |
| DOI | 10.1039/d4md00063c |
| 通讯作者 | Ren, Jianfeng(Jianfeng.Ren@nottingham.edu.cn) ; Hirst, Jonathan D.(jonathan.hirst@nottingham.ac.uk) ; Xie, Hua(hxie@simm.ac.cn) ; Tang, Bencan(Bencan.Tang@nottingham.edu.cn) |
| 英文摘要 | Overactivation of the rat sarcoma virus (RAS) signaling is responsible for 30% of all human malignancies. Son of sevenless 1 (SOS1), a crucial node in the RAS signaling pathway, could modulate RAS activation, offering a promising therapeutic strategy for RAS-driven cancers. Applying machine learning (ML)-based virtual screening (VS) on small-molecule databases, we selected a random forest (RF) regressor for its robustness and performance. Screening was performed with the L-series and EGFR-related datasets, and was extended to the Chinese National Compound Library (CNCL) with more than 1.4 million compounds. In addition to a series of documented SOS1-related molecules, we uncovered nine compounds that have an unexplored chemical framework and displayed inhibitory activity, with the most potent achieving more than 50% inhibition rate in the KRAS G12C/SOS1 PPI assay and an IC50 value in the proximity of 20 mu g mL-1. Compared with the manner that known inhibitory agents bind to the target, hit compounds represented by CL01545365 occupy a unique pocket in molecular docking. An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors. Machine learning enabled ligand-based virtual screening is a valuable tool in discovering effective SOS1 inhibitors. |
| WOS关键词 | RAS ACTIVATOR SON ; BI 1701963 ; POTENT ; KRAS |
| 资助项目 | National Key Research and Development Program of China[CM2025] ; National Key Research and Development Program of China[2020Z092] ; Ningbo Science and Technology Bureau[2022 J171] ; Ningbo Natural Science Foundation Programme[22171153] ; Ningbo Natural Science Foundation Programme[21502101] ; National Natural Science Foundation of China ; Ministry of Science and Technology of the People's Republic of China[2018YFE0101700] ; National Key R&D Program of Intergovernmental Kay Projects[2014A22010] ; Ningbo Municipal Key Laboratory on Clean Energy Conversion Technologies[2020E10018] ; Zhejiang Provincial Key Laboratory for Carbonaceous Waste Processing and Process Intensification Research - Zhejiang Provincial Department of Science and Technology ; Department of Science, Innovation and Technology (DSIT) ; Royal Academy of Engineering under the Chairs in Emerging Technologies scheme ; University of Nottingham, England ; University of Nottingham Ningbo China |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001191397200001 |
| 出版者 | ROYAL SOC CHEMISTRY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/310511]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Ren, Jianfeng; Hirst, Jonathan D.; Xie, Hua; Tang, Bencan |
| 作者单位 | 1.Univ Birmingham, Sch Math, Watson Bldg, Birmingham B15 2TT, England 2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.Univ Nottingham, Fac Med & Hlth Sci, Malaysia Campus, Semenyih 43500, Malaysia 5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 6.Univ Nottingham, Sch Chem, Univ Pk, Nottingham NG7 2RD, England 7.Univ Nottingham Ningbo China, Nottingham Ningbo China Beacons Excellence Res & I, Dept Chem & Environm Engn, Key Lab Carbonaceous Waste Proc & Proc Intensifica, R China,199 Taikang East Rd, Ningbo 315100, Peoples R China |
| 推荐引用方式 GB/T 7714 | Duo, Lihui,Chen, Yi,Liu, Qiupei,et al. Discovery of novel SOS1 inhibitors using machine learning[J]. RSC MEDICINAL CHEMISTRY,2024,15(4):1392-1403. |
| APA | Duo, Lihui.,Chen, Yi.,Liu, Qiupei.,Ma, Zhangyi.,Farjudian, Amin.,...&Tang, Bencan.(2024).Discovery of novel SOS1 inhibitors using machine learning.RSC MEDICINAL CHEMISTRY,15(4),1392-1403. |
| MLA | Duo, Lihui,et al."Discovery of novel SOS1 inhibitors using machine learning".RSC MEDICINAL CHEMISTRY 15.4(2024):1392-1403. |
入库方式： OAI收割
来源：上海药物研究所
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