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. 2024 Sep 26;14(10):519.
doi: 10.3390/metabo14100519.

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

Affiliations

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

Adrián Camilo Rodríguez-Ararat et al. Metabolites. .

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 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.

Keywords: DENV3; MD simulations; MM/GBSA; NS5; ZIKV; compound library; lycorine; molecular docking.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
“Front view” of the overall structure of the DENV-3 RdRp (PDB code 5f3z) with lycorine analog LYCS505-214 as substrate. A ribbon diagram of the RdRp based on the report by Noble et al. (pdb entry 5F3Z) [17,18]. Interaction between LYCS505-214 (gray molecule) and the active-site residues (Asp663 and Asp664 from the GDD motif, represented as sticks), palm domain (green). The fingers and thumb domains are colored blue and yellow, respectively. The priming loop is colored red, and zinc atoms (gray). Left: Lycorine-(S) and lycorine-(R) enantiomer base structure, benzodioxol group (A), points essential for activity (B,C) [16,19]; anchor points (R1, R2, R3) and enantiomer points (D,E) used in this investigation.
Figure 2
Figure 2
General workflow of molecular docking calculations. Target DENV3 and ZIKV 3D structure preparation and structure comparison. Lycorine analog library ligand preparation: protonation states and partial charges. Screening round by molecular docking, ADMET score, and molecular dynamics.
Figure 3
Figure 3
Molecular docking results: close-up view of dual lycorine analog 728-210 enantiomers R (cyan) and S (pink) at the RdRp binding site N-pocket. Interacting residues are shown in green sticks, with hydrogen bonds (yellow), π-π stacking (cyan), salt bridges (pink), and MMGBSA binding free energy profiles, highlighting the interacting amino acid residues (dashes); DENV3 (A) and ZIKV (B) RdRp.
Scheme 1
Scheme 1
Chemical structures and activity data for Lycorine analogs LYCR728-210 and LYCR728-212. The top image represents the core structure of the Lycorine scaffold with labeled functional groups R1, R2, and R3. The table below shows specific modifications of the analogs, including the R1(1), R2(1), and R3(2) substituents, along with their corresponding XP GScore, rule of 5 compliance, and synthetic difficulty (SynthDiff) scores. Notably, LYCR728-210 and LYCR728-212 differ slightly in their R3(2) substituents, resulting in distinct XP GScores, highlighting key differences in their predicted biological activity.
Figure 4
Figure 4
MD simulation results at a 500 ns timescale for LYCR728-210 and LYCR728-212 complexes with NS5 RdRp. (A) RMSD of NS5 RdRp complexes with LYCR728-210 (left) and LYCR728-212 (right). (B) RMSD of ligands LYCR728-210 (left) and LYCR728-212 (right) during the simulation. (C) RMSF of residues in NS5 RdRp in complex with LYCR728-210 (left) and LYCR728-212 (right). The orange line represents DENV3, and the blue line represents ZIKV. The highlighted regions in (C) correspond to the GDD catalytic active site (purple box) and the priming loop (red box), showing significant fluctuations.
Figure 5
Figure 5
Comparative MD simulation results at 500 ns timescale of DENV and ZIKV NS5 RdRP proteins in complex with LYCR728-212 and LYCR728-210 ligands. (A) PCA, SASA, radius of gyration, and hydrogen bond analysis of DENV NS5 RdRP protein bound to LYCR728-212. (B) Similar analysis for ZIKV NS5 RdRP protein bound to LYCR728-212. (C) Analysis of DENV NS5 RdRP protein with LYCR728-210. (D) Corresponding analysis for ZIKV NS5 RdRP protein with LYCR728-210. PCA plots show protein flexibility across PC1 and PC2 with time progression (blue to yellow). SASA plots indicate solvent exposure over time, Rg plots reflect protein compactness, and hydrogen bond plots show dynamic ligand–protein interactions across the simulation.

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