Identification of Montelukast as flavivirus NS2B-NS3 protease inhibitor by inverse virtual screening and experimental validation.

Hailun Jiang, Yaoliang Zhang, Yuming Wu, Jiawei Cheng, Shasha Feng, Jian Wang, Xuejun Wang, Maosheng Cheng

Journal: Biochemical and biophysical research communications 2022;606():87-93

PMID: 35339757

Full Text on Elsevier Science View on PubMed

Abstract

Flavivirus, such as Dengue Virus (DENV) and Zika virus (ZIKV), infects millions of people and cause the death of thousands of people every year. Despite many efforts, there is no approved anti-flaviviral treatment available. In particular, some antiflavivirus compounds were investigated the cellular activities of DENV and ZIKV, but lacking the exploration of specific target enzyme, thereby resulting in the hindrance of structure-based drug design. One example is Montlukast, which was found to inhibit the replicon replication in DENV and ZIKV infected cells, with EC values as 1.03 μM (DENV) and 1.14 μM (ZIKV), while the underlying mechanism remains unclear. In our study, the inhibitory mechanisms of Montelukast against the replicon replication of DENV and ZIKV infected cells were studied by using in silico approaches including inverse virtual screening (IVS), molecular dynamics (MD) simulations and binding free energy calculation, and validated through in vitro protease assay, confirming Montelukast could bind to NS2B-NS3 proteases of DENV and ZIKV as a competitive inhibitor (IC for DENV: 25.65 μM, for ZIKV: 15.57 μM). Moreover, Montelukast has no potential off-target effect on NS2B-NS3 protease from thrombin and trypsin inhibitory assay. Overall, Montelukast may be used as a potential candidate to block NS2B-NS3 protease as well as lead for structural modification.

Address: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, 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; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.; Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, 100850, China.; Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, 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; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].; Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, 100850, China. Electronic address: [email protected].; Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, 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; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].

DOI: 10.1016/j.bbrc.2022.03.064

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MeSH Terms: Acetates, Antiviral Agents, Cyclopropanes, Enzyme Inhibitors, Flavivirus, Humans, Peptide Hydrolases, Protease Inhibitors, Quinolines, Sulfides, Viral Nonstructural Proteins, Zika Virus, Zika Virus Infection