2. Academic Validation
  3. Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family

Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family

  • J Med Chem. 2021 Oct 28;64(20):15111-15125. 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
Affiliations

Affiliations

  • 1 Center for Systems Biology, Department of Bioinformatics, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, China.
  • 2 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.
  • 3 School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, China.
  • 4 University of Chinese Academy of Sciences (UCAS), 19 Yuquan Road, Beijing 100049, China.
  • 5 Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, 1 Keji Road, Fuzhou 350117, China.
  • 6 Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4L8, Canada.
  • 7 Ensem Therapeutics, Inc., 200 Boston Avenue, Medford, Massachusetts 02155, United States.
  • 8 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.
  • 9 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
PMID: 34668699 DOI: 10.1021/acs.jmedchem.1c01076
Abstract

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.

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