Identification of Zika virus NS2B-NS3 protease and NS5 polymerase inhibitors by structure-based virtual screening of FDA-approved drugs

• Published in: Journal of biomolecular structure & dynamics 2024-10, Vol.42 (15), p.8073-8088
• Main Authors: Ezzemani, Wahiba, Altawalah, Haya, Windisch, Marc, Ouladlahsen, Ahd, Saile, Rachid, Kettani, Anass, Ezzikouri, Sayeh
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Catalytic Domain; DEAD-box RNA Helicases; Drug Approval; drug design; Humans; Hydrogen Bonding; Molecular Docking Simulation; Molecular Dynamics Simulation; NS2B-NS3; NS5 RdRp; Nucleoside-Triphosphatase; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protein Binding; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - chemistry; RNA-Dependent RNA Polymerase - metabolism; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Structure-Activity Relationship; United States; United States Food and Drug Administration; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism; Viral Proteases; virtual screening; Zika virus; Zika Virus - drug effects; Zika Virus - enzymology; Zika Virus Infection - drug therapy; Zika Virus Infection - virology
• ISSN: 0739-1102; 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2023.2242963

Zika virus (ZIKV) is a mosquito-borne human flavivirus responsible that causing emergency outbreaks in Brazil. ZIKV is suspected of causing Guillain-Barre syndrome in adults and microcephaly. The NS2B-NS3 protease and NS5 RNA-dependent RNA polymerase (RdRp), central to ZIKV multiplication, have been identified as attractive molecular targets for drugs. We performed a structure-based virtual screening of 2,659 FDA-approved small molecule drugs in the DrugBank database using AutoDock Vina in PyRx v0.8. Accordingly, 15 potential drugs were selected as ZIKV inhibitors because of their high values (binding affinity - binding energy) and we analyzed the molecular interactions between the active site amino acids and the compounds. Among these drugs, tamsulosin was found to interact most efficiently with NS2B/NS3 protease, as indicated by the lowest binding energy value (−8.27 kJ/mol), the highest binding affinity (−5.7 Kcal/mol), and formed H-bonds with amino acid residues TYRB130, SERB135, TYRB150. Furthermore, biotin was found to interact most efficiently with NS5 RdRp with a binding energy of −150.624 kJ/mol, a binding affinity of −5.6 Kcal/mol, and formed H-bonds with the amino acid residues ASPA665 and ASPA540. In vitro, in vivo, and clinical studies are needed to demonstrate anti-ZIKV safety and the efficacy of these FDA-approved drug candidates. Communicated by Ramaswamy H. Sarma