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

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 to -11.01 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.

Automated summary

This study utilized molecular simulations to explore potential therapeutic compounds against the Zika virus from the Azadirachta indica plant. Four common bioflavonoids were identified as promising inhibitors with substantial binding energy and interactions with essential residues of the Zika virus proteins. Molecular dynamics simulations confirmed the stability of the docked poses, and the calculated binding free energy further supported the predicted complex stability. These compounds are recommended for further experimental assessment.