Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F22%3A00557061" target="_blank" >RIV/86652036:_____/22:00557061 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.mdpi.com/1420-3049/27/8/2562" target="_blank" >https://www.mdpi.com/1420-3049/27/8/2562</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/molecules27082562" target="_blank" >10.3390/molecules27082562</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecules

ISSN

1420-3049

e-ISSN

1420-3049

Svazek periodika

27

Číslo periodika v rámci svazku

8

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

25

Strana od-do

2562

Kód UT WoS článku

000786775600001

EID výsledku v databázi Scopus

2-s2.0-85128801747