Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family,Journal of Medicinal Chemistry

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Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-20 , DOI: 10.1021/acs.jmedchem.1c01076
Huimin Zhang _{1,

2,

3,

4} , Jixiao He ₁ , Guang Hu ₁ , Fei Zhu ₁ , Hao Jiang _{2,

4} , Jing Gao _{2,

4} , Hu Zhou _{2,

4} , Hua Lin ₅ , Yingjuan Wang ₁ , Kaixian Chen _{2,

3,

4} , Fanwang Meng ₆ , Minghong Hao ₇ , Kehao Zhao ₈ , Cheng Luo _{2,

3,

4,

9} , Zhongjie Liang ₁

Affiliation

Center for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.
Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, China.
University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China.
Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, 1 Keji Road, Fuzhou 350117, China.
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4L8, Canada.
Ensem Therapeutics, Inc., 200 Boston Avenue, Medford, Massachusetts 02155, United States.
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.

Post-translational modification (PTM) on protein plays important roles in the regulation of cellular function and disease pathogenesis. The systematic analysis of PTM dynamics presents great opportunities to enlarge the target space by PTM allosteric regulation. Here, we presented a framework by integrating the sequence, structural topology, and particular dynamics features to characterize the functional context and druggabilities of PTMs in the well-known kinase family. The machine learning models with these biophysical features could successfully predict PTMs. On the other hand, PTMs were identified to be significantly enriched in the reported allosteric pockets and the allosteric potential of PTM pockets were thus proposed through these biophysical features. In the end, the covalent inhibitor DC-Srci-6668 targeting the PTM pocket in c-Src kinase was identified, which inhibited the phosphorylation and locked c-Src in the inactive state. Our findings represent a crucial step toward PTM-inspired drug design in the kinase family.

中文翻译：

翻译后修饰的动力学激发激酶家族的药物设计

蛋白质的翻译后修饰 (PTM) 在调节细胞功能和疾病发病机制中起着重要作用。PTM 动力学的系统分析为通过 PTM 变构调节扩大目标空间提供了很好的机会。在这里，我们通过整合序列、结构拓扑和特定动力学特征提出了一个框架，以表征众所周知的激酶家族中 PTM 的功能背景和成药性。具有这些生物物理特征的机器学习模型可以成功预测 PTM。另一方面，PTM 被鉴定为在报告的变构口袋中显着富集，因此通过这些生物物理特征提出了 PTM 口袋的变构潜力。到底，鉴定了靶向 c-Src 激酶中 PTM 口袋的共价抑制剂 DC-Srci-6668，其抑制磷酸化并将 c-Src 锁定在非活性状态。我们的发现代表了激酶家族中 PTM 启发药物设计的关键一步。

更新日期：2021-10-28

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