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Discovery of highly potent DENV NS2B-NS3 covalent inhibitors containing a phenoxymethylphenyl residue.
Biochem Biophys Res Commun. 2022 10 30; 627:214-219.BB

Abstract

Dengue virus (DENV) has developed rapidly in the past few decades and has been becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of relevant proteins makes it the most promising target for anti-DENV drug discovery, although none of NS2B-NS3 inhibitors have been approved for the market so far. In this study, potent NS2B-NS3 covalent inhibitors were discovered via chemical modification of a published covalent inhibitor WSL-01 (IC50 = 129 nM), yielding promising analogs WSL-75 and WSL-84 (IC50 = 24.8 nM and IC50 = 32.89 nM, respectively) with more than 10-fold increased enzymatic activities compared to the lead compound, and no evident cellular toxicity was observed. 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, which would be beneficial for novel NS2B-NS3 inhibitory development.

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Authors+Show Affiliations

Cheng J
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Feng S
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Zhang Y
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Ding T
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Jiang H
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Zhang Z
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Wang J
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Wang X
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Cheng M
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: mscheng@syphu.edu.cn.

MeSH

Antiviral AgentsDengue VirusMolecular Docking SimulationProtease InhibitorsSerine EndopeptidasesViral Nonstructural Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

36058105

Citation

Cheng, Jiawei, et al. "Discovery of Highly Potent DENV NS2B-NS3 Covalent Inhibitors Containing a Phenoxymethylphenyl Residue." Biochemical and Biophysical Research Communications, vol. 627, 2022, pp. 214-219.
Cheng J, Feng S, Zhang Y, et al. Discovery of highly potent DENV NS2B-NS3 covalent inhibitors containing a phenoxymethylphenyl residue. Biochem Biophys Res Commun. 2022;627:214-219.
Cheng, J., Feng, S., Zhang, Y., Ding, T., Jiang, H., Zhang, Z., Wang, J., Wang, X., & Cheng, M. (2022). Discovery of highly potent DENV NS2B-NS3 covalent inhibitors containing a phenoxymethylphenyl residue. Biochemical and Biophysical Research Communications, 627, 214-219. https://doi.org/10.1016/j.bbrc.2022.08.060
Cheng J, et al. Discovery of Highly Potent DENV NS2B-NS3 Covalent Inhibitors Containing a Phenoxymethylphenyl Residue. Biochem Biophys Res Commun. 2022 10 30;627:214-219. PubMed PMID: 36058105.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of highly potent DENV NS2B-NS3 covalent inhibitors containing a phenoxymethylphenyl residue. AU - Cheng,Jiawei, AU - Feng,Shasha, AU - Zhang,Yaoliang, AU - Ding,Tong, AU - Jiang,Hailun, AU - Zhang,Zhigang, AU - Wang,Jian, AU - Wang,Xuejun, AU - Cheng,Maosheng, Y1 - 2022/08/26/ PY - 2022/08/16/received PY - 2022/08/21/accepted PY - 2022/9/5/pubmed PY - 2022/9/14/medline PY - 2022/9/4/entrez KW - Covalent inhibitor KW - Dengue virus (DENV) KW - Molecular simulation KW - NS2B-NS3 SP - 214 EP - 219 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 627 N2 - Dengue virus (DENV) has developed rapidly in the past few decades and has been becoming the most widespread arbovirus in the world. The vital role of NS2B-NS3 in virus replication and maturation of relevant proteins makes it the most promising target for anti-DENV drug discovery, although none of NS2B-NS3 inhibitors have been approved for the market so far. In this study, potent NS2B-NS3 covalent inhibitors were discovered via chemical modification of a published covalent inhibitor WSL-01 (IC50 = 129 nM), yielding promising analogs WSL-75 and WSL-84 (IC50 = 24.8 nM and IC50 = 32.89 nM, respectively) with more than 10-fold increased enzymatic activities compared to the lead compound, and no evident cellular toxicity was observed. 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, which would be beneficial for novel NS2B-NS3 inhibitory development. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/36058105/Discovery_of_highly_potent_DENV_NS2B_NS3_covalent_inhibitors_containing_a_phenoxymethylphenyl_residue_ DB - PRIME DP - Unbound Medicine ER -