Discovery of novel covalent stabilizers for p53 Y220C using structure-based drug discovery methods
文献类型：期刊论文
| 作者 | Wen, Yiming1,2,5,6; Xu, Peijia3,6; Chen, Yijie4,5; Meng, Jingyi4,5; Zheng, Mingyue1,4,5,6 ; Zhang, Sulin1,5; Teng, Dan1,5; Li, Xutong1,5
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| 刊名 | MOLECULAR DIVERSITY
 |
| 出版日期 | 2025-02-13 |
| 页码 | 14 |
| 关键词 | p53 Y220C Covalent stabilizer Virtual screening Molecular dynamics DNA binding Structure-activity relationship Cancer therapy |
| ISSN号 | 1381-1991 |
| DOI | 10.1007/s11030-024-11095-1 |
| 英文摘要 | The p53 Y220C mutation, a prevalent structural variant in human cancers, compromises DNA binding and tumor suppressor functions by destabilizing the protein structure. Leveraging a combined approach of structure-based virtual screening, molecular dynamics simulations, and in vitro assays, we have identified C8, a racemic compound with an indole core and alpha, beta-unsaturated carbonyl groups, as a covalent stabilizer for p53 Y220C. Protein thermal shift and homogeneous time-resolved fluorescence assays confirmed that C8 and its analogs selectively bind to p53 Y220C and restore its DNA binding ability. Subsequent molecular dynamics simulations and structure-activity relationship analyses showed that both enantiomers of C8 form covalent bonds with Cys124 and Cys220, stabilizing the mutant structure. C8 and its analogs emerge as promising lead candidates for restoring the Y220C mutant's transcriptional function, highlights the potential of this scaffold for further optimization into p53 Y220C-targeted therapeutics. |
| WOS关键词 | MUTATIONS ; CANCER ; RESCUE ; MUTANT ; DATABASE ; DOCKING |
| 资助项目 | National Key Research and Development Program of China[2022YFC3400504] ; National Key Research and Development Program of China[2023YFC2305904] ; National Key Research and Development Program of China[XDB0830203] ; National Key Research and Development Program of China[XDB0830200] ; Strategic Priority Research Program of the Chinese Academy of sciences[82204278] ; Strategic Priority Research Program of the Chinese Academy of sciences[T2225002] ; Strategic Priority Research Program of the Chinese Academy of sciences[82273855] ; National Natural Science Foundation of China[E2G805H] ; SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program ; Shanghai Municipal Science and Technology Major Project[2023296] ; Youth Innovation Promotion Association CAS[GZC20232846] ; Postdoctoral Fellowship Program of CPSF[2024M763419] ; China Postdoctoral Science Foundation ; Shanghai Advanced Research Institute, Chinese Academy of Science, China |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001420101000001 |
| 出版者 | SPRINGER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316200]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Teng, Dan; Li, Xutong |
| 作者单位 | 1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China 3.East China UNormal niv, Sch Pharm, Shanghai 200237, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xianlin Rd, Nanjing 210023, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wen, Yiming,Xu, Peijia,Chen, Yijie,et al. Discovery of novel covalent stabilizers for p53 Y220C using structure-based drug discovery methods[J]. MOLECULAR DIVERSITY,2025:14. |
| APA | Wen, Yiming.,Xu, Peijia.,Chen, Yijie.,Meng, Jingyi.,Zheng, Mingyue.,...&Li, Xutong.(2025).Discovery of novel covalent stabilizers for p53 Y220C using structure-based drug discovery methods.MOLECULAR DIVERSITY,14. |
| MLA | Wen, Yiming,et al."Discovery of novel covalent stabilizers for p53 Y220C using structure-based drug discovery methods".MOLECULAR DIVERSITY (2025):14. |
入库方式： OAI收割
来源：上海药物研究所
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