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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

Kumar, Sanjay
Autor Kumar, Sanjay School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India Center for Bioinformatics, Computational and Systems Biology, Pathfinder Research and Training Foundation, Greater Noida 201308, India
El-Kafrawy, Sherif A
Autor El-Kafrawy, Sherif A ORCID Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 128442, Jeddah 21362, Saudi Arabia Department of Medical Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Bharadwaj, Shiv
Autor Bharadwaj, Shiv ORCID Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences v.v.i., BIOCEV Research Center, 252 50 Vestec, Czech Republic
Maitra, S S
Autor Maitra, S S School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
Alandijany, Thamir A
Autor Alandijany, Thamir A ORCID Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 128442, Jeddah 21362, Saudi Arabia Department of Medical Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Faizo, Arwa A
Autor Faizo, Arwa A Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 128442, Jeddah 21362, Saudi Arabia Department of Medical Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Khateb, Aiah M
Autor Khateb, Aiah M Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 128442, Jeddah 21362, Saudi Arabia Medical Laboratory Technology Department, College of Applied Medical Sciences, Taibah University, Medina 42353, Saudi Arabia
Dwivedi, Vivek Dhar
Autor Dwivedi, Vivek Dhar ORCID Center for Bioinformatics, Computational and Systems Biology, Pathfinder Research and Training Foundation, Greater Noida 201308, India Institute of Advanced Materials, IAAM, 59053 Ulrika, Sweden
Azhar, Esam I
Autor Azhar, Esam I ORCID Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 128442, Jeddah 21362, Saudi Arabia Department of Medical Laboratory Sciences, Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

Molecules. 2022 ; 27 (8) : . [pub] 20220415

ISSN 1420-3049
Medvik
Zdroj

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 (ZIKVpro) and NS5 RNA dependent RNA polymerase (ZIKVRdRp) 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 to -11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKVpro (B:His51, B:Asp75, and B:Ser135) and ZIKVRdRp (Asp540, Ile799, and Asp665) by comparison to the reference compounds, O7N inhibitor (ZIKVpro) and Sofosbuvir inhibitor (ZIKVRdRp). 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 ZIKVpro and ZIKVRdRp against ZIKV for further experimental assessment.

MeSH
antivirové látky chemie MeSH
Azadirachta * chemie MeSH
flavonoidy chemie MeSH
infekce virem zika * farmakoterapie MeSH
inhibitory proteas chemie MeSH
lidé MeSH
olovo farmakologie MeSH
proteasy farmakologie MeSH
RNA-dependentní RNA-polymerasa MeSH
simulace molekulového dockingu MeSH
virové nestrukturální proteiny metabolismus MeSH
virus zika * MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH

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