Integrated machine-learning methods for identification of Hepatitis C viral IRES sub-domain-IIa inhibitors

Hepatitis C virus (HCV) is a positive-strand RNA virus with an envelope, classified under the genus Hepacivirus within the Flaviviridae family. The virus's genome contains a 5′ untranslated region (UTR), which includes the Internal Ribosome Entry Site (IRES). Inhibition of this region may represent a crucial approach to developing effective treatments for HCV infection. In the current study, FDA-approved drug libraries were collected, curated, and processed using the Mol2Mol package of Reinvent4 to generate a pool of new molecules. The resulting compounds were then sorted using the Tanimoto similarity score. Further refinement was achieved through molecular docking, pharmacokinetic analysis, and toxicity assessment, ultimately identifying four compounds with significant potential for RNA binding. The ligands, identified as 6-Methoxy-2-methyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,7-diol (M1), 2-Hydroxy-5-((R)-1-hydroxy-2-(((S)-1-phenylethyl)amino)ethyl)benzamide (M2), (S)-2-Amino-N-((S)-2-(2,5-dimethoxyphenyl)-2-hydroxyethyl)-3-methylbutanamide (M3), and 1-(Isopropyl-D-alanyl)octahydro-1H-indole-2-carboxylic acid (M4), demonstrated excellent binding to the IRES subdomain IIa. Their respective binding scores were −31.7912, −52.3670, −29.2841, and −35.2013 kcal/mol. A 200 ns period of molecular dynamics simulation was conducted to explore the dynamic behavior of RNA and the four proposed compounds. Various statistical analyses substantiated the stability and rigidity of the complexes formed between the RNA and the proposed compounds. The free energy landscape and Molecular Mechanics with Generalized Born and Surface Area solvation (MM-GBSA) analyses further demonstrated the potential of these molecules as inhibitors. In conclusion, the final four compounds identified in this study show promise as potential inhibitors targeting the Hepatitis C Virus Internal Ribosome Entry Site, warranting further investigation for their therapeutic potential in HCV treatment.