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

Area of Science:

• Virology
• Medicinal Chemistry
• Computational Biology

Background:

• Dengue (DENV) and Zika (ZIKV) viruses pose significant global health threats.
• Effective vaccines and therapeutics are lacking for DENV and ZIKV infections.
• The conserved NS5 RNA-dependent RNA polymerase (RdRp) is a key target for antiviral development.

Purpose of the Study:

• To design and identify potential inhibitors of DENV and ZIKV NS5-RdRp.
• To explore lycorine analogs as non-nucleoside inhibitors targeting the allosteric N-pocket.
• To evaluate the binding affinity and drug-likeness of designed compounds.

Main Methods:

• Integrated in silico approach: combinatorial chemistry, docking, molecular dynamics simulations, MM/GBSA, and ADMET studies.
• Targeting the allosteric N-pocket of DENV3-RdRp and ZIKV-RdRp.
• Design and evaluation of lycorine analogs with S-enantiomers (LYCS) and R-enantiomers (LYCR).

Main Results:

• 12 lycorine analogs exhibited strong binding free energy (<-9.00 kcal/mol), outperforming ribavirin.
• Promising ADMET scores (<4.00) were predicted for the designed analogs.
• Specific analogs (LYCR728-210, LYCS728-210, LYCR728-212, LYCS505-214) showed binding to both DENV3 and ZIKV targets.

Conclusions:

• Lycorine-based analogs, particularly with different enantiomers, are promising non-nucleoside inhibitors of NS5-RdRp.
• Enantiomers may exhibit distinct pharmacological and toxicological profiles.
• These findings pave the way for developing novel antiviral agents against DENV and ZIKV.