Identification and In Silico Binding Study of a Highly Potent DENV NS2B-NS3 Covalent Inhibitor

  • ACS Med Chem Lett. 2022 Mar 8;13(4):599-607. doi: 10.1021/acsmedchemlett.1c00653.
Xincheng Lin  1  2  3 ,  Jiawei Cheng  1  2  3 ,  Yuming Wu  4 ,  Yaoliang Zhang  1  2  3 ,  Hailun Jiang  1  2  3 ,  Jian Wang  1  2  3 ,  Xuejun Wang  4 ,  Maosheng Cheng  1  2  3
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3. Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4. Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
PMID: 35450371 DOI: 10.1021/acsmedchemlett.1c00653
Abstract

Dengue Virus (DENV), an arthropod-borne Flavivirus, has developed rapidly in the past few decades and becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of Viral Proteins makes it the most promising target for anti-DENV drug discovery. In the current work, a potent NS2B-NS3 covalent inhibitor 23 (IC50 = 6.0 nM, k inac/K i = 1581 M-1 s-1) was discovered through the chemical modification of a published covalent inhibitor 1 (IC50 = 500 nM, k inac/K i = 156.1 M-1 s-1), followed by in vitro assay. Further comprehensive structure-activity relationship analysis through covalent docking and molecular dynamics simulation provides informative understanding of the binding modes of covalent inhibitors targeting NS2B-NS3.

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