Non-Nucleoside Lycorine-Based Analogs as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis

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dc.contributor.authorRodríguez-Ararat, Adrián Camiloen
dc.contributor.authorHayek-Orduz, Yasseren
dc.contributor.authorVásquez, Andrés-Felipeen
dc.contributor.authorSierra-Hurtado, Felipeen
dc.contributor.authorVillegas-Torres, María-Franciscaen
dc.contributor.authorCaicedo-Burbano, Paola A.en
dc.contributor.authorAchenie, Luke E. K.en
dc.contributor.authorBarrios, Andrés Fernando Gonzálezen
dc.date.accessioned2024-10-25T13:56:15Zen
dc.date.available2024-10-25T13:56:15Zen
dc.date.issued2024-09-26en
dc.date.updated2024-10-25T13:42:27Zen
dc.description.abstractDengue (DENV) and Zika (ZIKV) virus continue to pose significant challenges globally due to their widespread prevalence and severe health implications. Given the absence of effective vaccines and specific therapeutics, targeting the highly conserved NS5 RNA-dependent RNA polymerase (RdRp) domain has emerged as a promising strategy. However, limited efforts have been made to develop inhibitors for this crucial target. In this study, we employed an integrated in silico approach utilizing combinatorial chemistry, docking, molecular dynamics simulations, MM/GBSA, and ADMET studies to target the allosteric N-pocket of DENV3-RdRp and ZIKV-RdRp. Using this methodology, we designed lycorine analogs with natural S-enantiomers (LYCS) and R-enantiomers (LYCR) as potential inhibitors of non-structural protein 5 (NS5) in DENV3 and ZIKV. Notably, 12 lycorine analogs displayed a robust binding free energy (<−9.00 kcal/mol), surpassing that of RdRp-ribavirin (<−7.00 kcal/mol) along with promising ADMET score predictions (<4.00), of which (LYCR728-210, LYCS728-210, LYCR728-212, LYCS505-214) displayed binding properties to both DENV3 and ZIKV targets. Our research highlights the potential of non-nucleoside lycorine-based analogs with different enantiomers that may present different or even completely opposite metabolic, toxicological, and pharmacological profiles as promising candidates for inhibiting NS5-RdRp in ZIKV and DENV3, paving the way for further exploration for the development of effective antiviral agents.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationRodríguez-Ararat, A.C.; Hayek-Orduz, Y.; Vásquez, A.-F.; Sierra-Hurtado, F.; Villegas-Torres, M.-F.; Caicedo-Burbano, P.A.; Achenie, L.E.K.; Barrios, A.F.G. Non-Nucleoside Lycorine-Based Analogs as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis. Metabolites 2024, 14, 519.en
dc.identifier.doihttps://doi.org/10.3390/metabo14100519en
dc.identifier.urihttps://hdl.handle.net/10919/121397en
dc.language.isoenen
dc.publisherMDPIen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleNon-Nucleoside Lycorine-Based Analogs as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysisen
dc.title.serialMetabolitesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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