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Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations
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SYSNO ASEP 0557061 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations Author(s) Kumar, S. (IN)
El-Kafrawy, S. (SA)
Bharadwaj, Shiv (BTO-N)
Maitra, S. (IN)
Alandijany, T. (SA)
Faizo, A. (SA)
Khateb, A. (SA)
Dwivedi, V. (SE)
Azhar, E. (SA)Number of authors 9 Article number 2562 Source Title Molecules. - : MDPI
Roč. 27, č. 8 (2022)Number of pages 25 s. Language eng - English Country CH - Switzerland Keywords Zika virus ; NS2B-NS3 protease ; NS5 RdRp ; therapeutics Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology Method of publishing Open access Institutional support BTO-N - RVO:86652036 UT WOS 000786775600001 EID SCOPUS 85128801747 DOI 10.3390/molecules27082562 Annotation Zika virus (ZIKV) has been characterized as one of many potential pathogens and placed under future epidemic outbreaks by the WHO. However, a lack of potential therapeutics can result in an uncontrolled pandemic as with other human pandemic viruses. Therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted a strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the NS2B-NS3 protease (ZIKV(pro)) and NS5 RNA dependent RNA polymerase (ZIKV(RdRp)) proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of the top four common bioflavonoids, viz. Rutin, Nicotiflorin, Isoquercitrin, and Hyperoside. These compounds showed substantial docking energy (-7.9 to11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKV(pro) (B:His(51), B:Asp(75), and B:Ser(135)) and ZIKV(RdRp) (Asp(540), Ile(799), and Asp(665)) by comparison to the reference compounds, O7N inhibitor (ZIKV(pro)) and Sofosbuvir inhibitor (ZIKV(RdRp)). Besides, long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals stability of the respective docked poses contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKV(pro) and ZIKV(RdRp) against ZIKV for further experimental assessment. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2023 Electronic address https://www.mdpi.com/1420-3049/27/8/2562
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