Dataset Information

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

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.

SUBMITTER: Lin X

PROVIDER: S-EPMC9014507 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Lin Xincheng X Cheng Jiawei J Wu Yuming Y Zhang Yaoliang Y Jiang Hailun H Wang Jian J Wang Xuejun X Cheng Maosheng M

ACS medicinal chemistry letters 20220308 4

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 thro ...[more]

PMID: 35450371

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Project description:Zika virus (ZIKV) is a mosquito-borne flavivirus that causes severe neurological disorders, such as microcephaly in fetuses. Most recently, an outbreak of ZIKV started in Brazil in 2015. To date, no therapeutic agents have been approved to treat ZIKV infection in the clinic. Here, we screened a small molecule inhibitor that can inhibit the function of ZIKV non-structural protein 2B (NS2B)-NS3 protease (ZIKV NS2B-NS3 protease), thereby interfering with viral replication and spread. First, we identified the half maximal inhibitory concentration (IC50) of compound 3 (14.01 μM), 8 (6.85 μM), and 9 (14.2 μM) and confirmed that they are all non-competitive inhibitors. In addition, we have used the blind molecular docking method to simulate the inhibition area of three non-competitive inhibitors (compound 3, 8, and 9) with the ZIKV NS2B-NS3 protease. The results indicated that the four allosteric binding residues (Gln139, Trp148, Leu150, and Val220) could form hydrogen bonds or non-bonding interactions most frequently with the three compounds. The interaction might induce the reaction center conformation change of NS2B-NS3 protease to reduce catalyzed efficiency. The concentration of compounds required to reduce cell viability by 50% (CC50), and the concentration of compounds required to inhibit virus-induced cytopathic effect by 50% (EC50) of three potential compounds are >200 μM, 2.15 μM (compound 3), > 200 μM, 0.52 μM (compound 8) and 61.48 μM, 3.52 μM (compound 9), and Temoporfin are 61.05 μM, 2 μM, respectively. To select candidate compounds for further animal experiments, we analyzed the selectivity index (SI) of compound 3 (93.02), 8 (384.61), 9 (17.46), and Temoporfin (30.53, FDA-approved drug against cancer). Compound 8 has the highest SI value. Therefore, compound 8 was selected for verification in animal models. In vivo, compound 8 significantly delayed ZIKV-induced lethality and illness symptoms and decreased ZIKV-induced weight loss in a ZIKV-infected suckling mouse model. We conclude that compound 8 is worth further investigation for use as a potential future therapeutic agent against ZIKV infection.

Dataset Information

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

Publications

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

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