Version 1
: Received: 4 July 2024 / Approved: 4 July 2024 / Online: 5 July 2024 (12:04:10 CEST)
How to cite:
Rodríguez-Ararat, A. C.; Hayek-Orduz, Y.; Vásquez, A. F.; Sierra-Hurtado, F.; Villegas-Torres, M.-F.; Caicedo-Burbano, P. A.; Achenie, L.-E.; Barrios, A. F. G. Non-Nucleoside Lycorine-Based Analogues as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis. Preprints2024, 2024070477. https://doi.org/10.20944/preprints202407.0477.v1
Rodríguez-Ararat, A. C.; Hayek-Orduz, Y.; Vásquez, A. F.; Sierra-Hurtado, F.; Villegas-Torres, M.-F.; Caicedo-Burbano, P. A.; Achenie, L.-E.; Barrios, A. F. G. Non-Nucleoside Lycorine-Based Analogues as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis. Preprints 2024, 2024070477. https://doi.org/10.20944/preprints202407.0477.v1
Rodríguez-Ararat, A. C.; Hayek-Orduz, Y.; Vásquez, A. F.; Sierra-Hurtado, F.; Villegas-Torres, M.-F.; Caicedo-Burbano, P. A.; Achenie, L.-E.; Barrios, A. F. G. Non-Nucleoside Lycorine-Based Analogues as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis. Preprints2024, 2024070477. https://doi.org/10.20944/preprints202407.0477.v1
APA Style
Rodríguez-Ararat, A. C., Hayek-Orduz, Y., Vásquez, A. F., Sierra-Hurtado, F., Villegas-Torres, M. F., Caicedo-Burbano, P. A., Achenie, L. E., & Barrios, A. F. G. (2024). Non-Nucleoside Lycorine-Based Analogues as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis. Preprints. https://doi.org/10.20944/preprints202407.0477.v1
Chicago/Turabian Style
Rodríguez-Ararat, A. C., Luke-E.K. Achenie and Andrés Fernando González Barrios. 2024 "Non-Nucleoside Lycorine-Based Analogues as Potential DENV/ZIKV NS5 Dual Inhibitors: Structure-Based Virtual Screening and Chemoinformatic Analysis" Preprints. https://doi.org/10.20944/preprints202407.0477.v1
Abstract
Dengue (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 of 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. This study 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.
Medicine and Pharmacology, Epidemiology and Infectious Diseases
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
