Identification of potential inhibitors targeting yellow fever virus helicase through ligand and structure-based computational studies

Yellow fever is a flavivirus having plus-sensed RNA which encodes a single polyprotein. Host proteases cut this polyprotein into seven nonstructural proteins including a vital NS3 protein. The present study aims to identify the most effective inhibitor against the helicase (NS3) using different adva...

Full description

Saved in:
Bibliographic Details
Published in:Journal of biomolecular structure & dynamics 2023-12, p.1-18
Main Authors: Zaib, Sumera, Rana, Nehal, Ali, Hafiz Saqib, Ur Rehman, Mujeeb, Awwad, Nasser S, Ibrahium, Hala A, Khan, Imtiaz
Format: Article
Language:English
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Yellow fever is a flavivirus having plus-sensed RNA which encodes a single polyprotein. Host proteases cut this polyprotein into seven nonstructural proteins including a vital NS3 protein. The present study aims to identify the most effective inhibitor against the helicase (NS3) using different advanced ligand and structure-based computational studies. A set of 300 ligands was selected against helicase by chemical structural similarity model, which are similar to -adenosyl-l-cysteine using infiniSee. This tool screens billions of compounds through a similarity search from in-built chemical spaces (CHEMriya, Galaxi, KnowledgeSpace and REALSpace). The pharmacophore was designed from ligands in the library that showed same features. According to the sequence of ligands, six compounds ( , , , , , and ) were taken for pharmacophore designing against helicase protein. Subsequently, compounds from the library which showed the best pharmacophore shared-features were docked using FlexX functionality of SeeSAR and their optibrium properties were analyzed. Afterward, their ADME was improved by replacing the unfavorable fragments, which resulted in the generation of new compounds. The selected best compounds ( , , and ) were docked using SeeSAR and their pharmacokinetics and toxicological properties were evaluated using SwissADME. The optimal inhibitor for yellow fever helicase was 2-amino- -(4-(dimethylamino)thiazol-2-yl)-4-methyloxazole-5-carboxamide ( ), which exhibits promising potential for drug development.Communicated by Ramaswamy H. Sarma.
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2023.2294839