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. 2025 May 27;18(6):806.
doi: 10.3390/ph18060806.

Unveiling Palmitoyl Thymidine Derivatives as Antimicrobial/Antiviral Inhibitors: Synthesis, Molecular Docking, Dynamic Simulations, ADMET, and Assessment of Protein-Ligand Interactions

Sarkar M A Kawsar  1 , Samiah Hamad Al-Mijalli  2 , Gassoumi Bouzid  3 , Emad M Abdallah  4 , Noimul H Siddiquee  5 , Mohammed A Hosen  1 , Mabrouk Horchani  6 , Houcine Ghalla  7 , Hichem B Jannet  6 , Yuki Fujii  8 , Yasuhiro Ozeki  9
Affiliations

Unveiling Palmitoyl Thymidine Derivatives as Antimicrobial/Antiviral Inhibitors: Synthesis, Molecular Docking, Dynamic Simulations, ADMET, and Assessment of Protein-Ligand Interactions

Sarkar M A Kawsar et al. Pharmaceuticals (Basel). .

Abstract

Background/Objectives: Nucleoside precursors and derivatives play pivotal roles in the development of antimicrobial and antiviral therapeutics. The 2022 global outbreak of monkeypox (Mpox) across more than 100 nonendemic countries underscores the urgent need for novel antiviral agents. This study aimed to synthesize and evaluate a series of 5'-O-(palmitoyl) derivatives (compounds 2-6), incorporating various aliphatic and aromatic acyl groups, for their potential antimicrobial activities. Methods: The structures of the synthesized derivatives were confirmed through physicochemical, elemental, and spectroscopic techniques. In vitro antibacterial efficacy was assessed, including minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) determinations for the most active compounds (4 and 5). The antifungal activity was evaluated based on mycelial growth inhibition. Density functional theory (DFT) calculations were employed to investigate the electronic and structural properties, including the global reactivity, frontier molecular orbital (FMO), natural bond orbital (NBO), and molecular electrostatic potential (MEP). Molecular docking studies were conducted against the monkeypox virus and the Marburg virus. The top-performing compounds (3, 5, and 6) were further evaluated via 200 ns molecular dynamics (MD) simulations. ADMET predictions were performed to assess drug-likeness and pharmacokinetic properties. Results: Compounds 4 and 5 demonstrated remarkable antibacterial activity compared with the precursor molecule, while most derivatives inhibited fungal mycelial growth by up to 79%. Structure-activity relationship (SAR) analysis highlighted the enhanced antibacterial/antifungal efficacy with CH3(CH2)10CO- and CH3(CH2)12CO-acyl chains. In silico docking revealed that compounds 3, 5, and 6 had higher binding affinities than the other derivatives. MD simulations confirmed the stability of the protein-ligand complexes. ADMET analyses revealed favorable drug-like profiles for all the lead compounds. Conclusions: The synthesized compounds 3, 5, and 6 exhibit promising antimicrobial and antiviral activities. Supported by both in vitro assays and comprehensive in silico analyses, these derivatives have emerged as potential candidates for the development of novel therapeutics against bacterial, fungal, and viral infections, including monkeypox and Marburg viruses.

Keywords: DFT; Marburg virus; microorganism; molecular dynamics simulation; monkeypox; thymidine.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Different derivatives are used as drugs with pyrimidine moieties.
Scheme 1
Scheme 1
Synthetic pathway. Dry Py, 0 °C, 6 h; DMAP, R1-Cl = various acyl halides, 0 °C to rt, stirred for 6−7 h (2–6).
Figure 2
Figure 2
Probable mechanism of the palmitoylation of thymidine.
Figure 3
Figure 3
MIC values of the compounds against pathogens. The data are presented as mean ± SD, and the values are represented for triplicate experiments. Statistically significant inhibition (p < 0.05) for the test compounds and reference antibiotic azithromycin.
Figure 4
Figure 4
MBC values of the compounds against pathogens. The data are presented as mean ± SD, and the values are represented for triplicate experiments. Statistically significant inhibition (p < 0.05) for the test compounds and reference antibiotic azithromycin.
Figure 5
Figure 5
Structure–activity studies of thymidine derivatives.
Figure 6
Figure 6
Membrane permeability with hydrophobic interactions between the bacterial outer membrane and peptidoglycan with compound 5.
Figure 7
Figure 7
Optimized structures and MEPs of all the studied systems (1–6). (a,c,e,g,i,k) indicate the active sites of the compounds, and (b,d,f,h,j,l) indicates the MEP of the compounds.
Figure 7
Figure 7
Optimized structures and MEPs of all the studied systems (1–6). (a,c,e,g,i,k) indicate the active sites of the compounds, and (b,d,f,h,j,l) indicates the MEP of the compounds.
Figure 7
Figure 7
Optimized structures and MEPs of all the studied systems (1–6). (a,c,e,g,i,k) indicate the active sites of the compounds, and (b,d,f,h,j,l) indicates the MEP of the compounds.
Figure 8
Figure 8
HOMO-LUMO is the surface of all the studied compounds (1–6) calculated at the B3LYP/6-311G+(d,p) level of theory.
Figure 8
Figure 8
HOMO-LUMO is the surface of all the studied compounds (1–6) calculated at the B3LYP/6-311G+(d,p) level of theory.
Figure 8
Figure 8
HOMO-LUMO is the surface of all the studied compounds (1–6) calculated at the B3LYP/6-311G+(d,p) level of theory.
Figure 9
Figure 9
NBO charges of all the studied compounds (1–6).
Figure 10
Figure 10
Binding mode of the most effective compound 5 in the binding cavity of the A42R profilin-like protein from the monkeypox virus.
Figure 11
Figure 11
Binding modes of docked compounds 1, 2, 3, 4, and 6 and the reference (acyclovir) in the binding cavity of the A42R profilin-like protein from the monkeypox virus.
Figure 12
Figure 12
Binding mode of the most effective compound, compound 6, in the binding cavity of the Marburg virus.
Figure 13
Figure 13
Binding modes of docked compounds 1, 2, 3, 4, and 5 and the reference (acyclovir) in the binding cavity of the Marburg virus.
Figure 14
Figure 14
The graph chart plotted above shows the values for RMSD (A), RMSF (B), Rg (C), and SASA (D) extracted from the data analysis trajectories by the MD simulation approach for the following ligands: ligand 3 (orange), ligand 5 (green), ligand 6 (sky blue), acyclovir (red), and apoprotein (blue).
Figure 15
Figure 15
The bar charts illustrate the correlation between the ligand and chain A of the 4QWO protein, as observed during the 200 ns simulation. Therefore, they demonstrated the interaction between the monkeypox virus 4QWO protein and four specific compounds: ligands 3 (A), 5 (B), and 6 (C) and acyclovir (control) (D).
Figure 15
Figure 15
The bar charts illustrate the correlation between the ligand and chain A of the 4QWO protein, as observed during the 200 ns simulation. Therefore, they demonstrated the interaction between the monkeypox virus 4QWO protein and four specific compounds: ligands 3 (A), 5 (B), and 6 (C) and acyclovir (control) (D).
Figure 16
Figure 16
Protein Cα RMSD (A), RMSF (B), Rg (C), and SASA (D) were found from a 200 ns MD trajectory through a simulation interaction diagram.
Figure 17
Figure 17
In these bar charts, the 4OR8 protein showed interactions with ligand 3 (A), ligand 5 (B), ligand 6 (C), and acyclovir (D) where the P-L interactions were determined during the 200 ns simulation period.
Figure 18
Figure 18
Illustrates the successive steps of conducting the present research.
See this image and copyright information in PMC

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