An in Silico Approach for Screening and Discovery of Drug Leads Targeting the Non-coding Regions of Enterovirus A71 RNA Genome

Abstract

Enterovirus A71 (EV-A71) is the aetiological agent of Hand, Foot and Mouth Disease (HFMD) in underage children leading to neurological conditions including brain encephalitis and acute flaccid paralysis. HFMD is prevalent both in the Asia- Pacific and African regions with 13.7 million cases recorded from epidemics in China between 2008 and 2015 (Puenpa et al., 2019). No antiviral drugs against EV-A71 exists. Treatment rather relies on symptomatic management, which remains ineffective. Recent advances highlight the potential of non-coding RNA in therapeutics as they play an extensive role in controlling protein expression. The aim of this study was to determine the three-dimesional structure of the non-coding regions of EV-A71 and perform molecular docking targeting these region to identify potential drug leads. The study modelled the three-dimensional structure of the 3’ UTR and 5’UTR of EV-A71 using a suite of webbased and standalone tools. Using MEME suite motif discovery, the study identified and provided the layout of significant motifs: five for the 5’ UTR and one for the 3’ UTR. Thirteen identified molecules; amantadine, ribavirin, baicalin, 7-hydroxy isoflavone, myricetin, kaempferol, taxifolin, diosmetin, dihydromyricetin, ursolic acid, baicalin, morin hydrate, and nobiletin with antiviral activity against enteroviruses were docked on the 3D structure of the 3’ and 5’ UTR via PatchDock, providing different docking positions and alternative potential drug targets. For the 5’ UTR motif 1 (5’- AGCYAGUGGGUWG-3’), present in domain II that binds hnRNP that stimulates translation and motif 5 (5’-AGCYAGUGGGUWG-3’), eIF4G and eIF4A binding site for ribosomal assembly, were the most significant potential drug targets. The 3’ UTR, which is crucial for replication, had one major motif (5’- UGGKSGURAAUKUG-3’) that formed a binding pocket. Nobiletin, baicalin, ursolic acid, and diosmetin had the lowest atomic contact energies indiacating higher affinity and specificity for EV-A71 UTRs (-496.03, -472.39, -445.52, and -394.16 kcal/mol, respectively). This work outlines the 3D structure of EV-A71 UTRs, the location of important motifs used in viral gene expression and translation, and potential drug target regions. Moreover, this work presents the potential compounds that can be used as combination therapy to drive fundamental research in therapeutics focusing on UTRs.