The hepatitis E virus- (HEV-) helicase as a novel drug-target was evaluated. While cell culture model was used for mutational\ncharacterization of helicase, in silico protein modeling and virtual screening were employed to identify helicase inhibitors. None of\nthe saturation mutant replicons significantly affected RNA replication. Notably,mutants encompassing the Walker motifs replicated\nas wild-type, showing indispensability of nucleotides conservation in viability compared to known criticality of amino acids. A\n3D modeling of HEV-helicase and screening of a compound dataset identified ten most promising inhibitors with drug likeness,\nnotably, JFD02650, RDR03130, and HTS11136 that interacted with Walker A residues Gly975, Gly978, Ser979, and Gly980. Our\nmodel building and virtual identification of novel helicase inhibitors warrant further studies towards developing anti-HEV drugs.
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