The discovery of Zika virus NS2B-NS3 inhibitors with antiviral activity via an integrated virtual screening approach

Mirza, Muhammad Usman and Alanko, Ida and Vanmeert, Michiel and Muzzarelli, Kendall M. and Salo-Ahen, Outi M. H. and Abdullah, Iskandar and Kovari, Iulia A. and Claes, Sandra and De Jonghe, Steven and Schols, Dominique and Schinazi, Raymond F. and Kovari, Ladislau C. and Trant, John F. and Ahmad, Sarfraz and Froeyen, Matheus (2022) The discovery of Zika virus NS2B-NS3 inhibitors with antiviral activity via an integrated virtual screening approach. European Journal of Pharmaceutical Sciences, 175. ISSN 0928-0987, DOI

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With expanding recent outbreaks and a lack of treatment options, the Zika virus (ZIKV) poses a severe health concern. The availability of ZIKV NS2B-NS3 co-crystallized structures paved the way for rational drug discovery. A computer-aided structure-based approach was used to screen a diverse library of compounds against ZIKV NS2B-NS3 protease. The top hits were selected based on various binding free energy calculations followed by perresidue decomposition analysis. The selected hits were then evaluated for their biological potential with ZIKV protease inhibition assay and antiviral activity. Among 26 selected compounds, 8 compounds showed promising activity against ZIKV protease with a percentage inhibition of greater than 25 and 3 compounds displayed similar to 50% at 10 mu M, which indicates an enrichment rate of approximately 36% (threshold IC50 < 10 mu M) in the ZIKV-NS2B-NS3 protease inhibition assay. Of these, only one compound (23) produced whole-cell anti-ZIKV activity, and the binding mode of 23 was extensively analyzed through long-run molecular dynamics simulations. The current study provides a promising starting point for the further development of novel compounds against ZIKV.

Item Type: Article
Funders: None
Uncontrolled Keywords: Virtual screening; Zika virus; NS2B-NS3 protease; Flavivirus; Protease inhibitor
Subjects: Q Science > QR Microbiology
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 22 Nov 2023 04:17
Last Modified: 03 Dec 2023 02:02

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