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. 2024 Mar;48(1):81-94.
doi: 10.1007/s12639-023-01639-x. Epub 2024 Feb 1.

3-styrylcoumarin scaffold-based derivatives as a new approach for leishmaniasis intervention: biological and molecular modeling studies

Andrés F Yepes  1 , Sara M Robledo  2 , Jorge Quintero-Saumeth  1 , Wilson Cardona-Galeano  1
Affiliations

3-styrylcoumarin scaffold-based derivatives as a new approach for leishmaniasis intervention: biological and molecular modeling studies

Andrés F Yepes et al. J Parasit Dis. 2024 Mar.

Abstract

Seven 3-styrylcoumarins were tested for antileishmanial activity against Leishmania (Viannia) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. The 3-methoxy-4-hydroxy coumarin derivative 6 was the most active with an IC50 of 40.5 µM, and did not reveal any conspicuous toxicity toward mammalian U-937 cells. Therefore, it may have potential to be considered as candidate for antileishmanial drug development. Further, among several druggable Leishmania targets, molecular docking studies revealed that compound 6 had docking preference by the N-myristoyltransferase (Lp-NMT) of Leishmania panamensis, showing a higher docking score of - 10.1 kcal mol-1 than positive controls and making this protein as a presumably druggable target for this compound. On the other hand, molecular dynamics simulations affirm the docking hypothesis, showing a conformational stability of the 6/Lp-NMT complex throughout 100 ns simulation. Moreover, the molecular mechanics/Poisson-Boltzmann surface area method also support the docking findings, revealing a total free energy of binding of - 47.26 ± 0.08 kcal mol-1, and identifying through energy decomposition analysis that those key aminoacids are contributing strongly to ligand binding. Finally, an optimal pharmacokinetic profile was also estimated for 6. Altogether, coumarin 6 could be addressed as starting point for further pharmacological studies concerning the therapeutic leishmaniasis intervention.

Keywords: 3-styrylcoumarins; Docking studies; In-silico pharmacokinetic evaluation; Leishmaniasis; Molecular modeling studies.

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Conflict of interest statement

Conflict of interestThe authors declare no conflict of interest, financial or otherwise.

Figures

Fig. 1
Fig. 1
Coumarins with antileishmanial activity: Aurapten (A), coumarins from Galipea panamensis (B–D), 7-glucocoumarin (E), 4-arylcoumarin (F)
Fig. 2
Fig. 2
Synthetic pathway to 3-styrylcoumarins
Fig. 3
Fig. 3
A Superimposition of the best binding modes of the coumarin 6 (in magenta) and two known NMT-modulators: myristoyl-CoA (in blue) and S-(2-oxo)pentadecyl-CoA (in orange) alongside Lp-NMT myristoyl-CoA binding pocket. Hydrophobic site (S1) and Hydrophilic site (S2). B Superimposed view of the best binding modes for coumarin (in magenta) and myristoyl-CoA (in blue) and S-(2-oxo)pentadecyl-CoA (in orange) (Color figure online)
Fig. 4
Fig. 4
2D ligand–protein interaction plot between coumarin 6 with residues inside the myristoyl-CoA binding pocket of Lp-NMT. Dotted lines indicate interactions between coumarin and amino acid residues in the Lp-NMT catalytic domain
Fig. 5
Fig. 5
Structural comparison between the active coumarin 6 (A) and NMT-inhibitors inhibitors S-(2-oxo)pentadecyl-Coa (B) and myristoyl-Coa (C). Magenta dotted line separates two possible key structural requirements for NMT-inhibition
Fig. 6
Fig. 6
A Analysis of RMSD trajectories for the 6/Lp-NMT complex throughout 100 ns all-atom MD simulation. B Evolution of the radius of gyration (Rg) for 6/Lp-NMT complex along 100 ns of MDs
Fig. 7
Fig. 7
A 3D surface plot for comparison the top-scoring docking pose (blue), and the best conformation (in red) of 6 after 100 ns MD simulations inside the myristoyl-CoA catalytic site. B The energy contributions per amino acid residue to the 6/Lp-NMT complex formation by MM-PBSA method (Color figure online)
Fig. 8
Fig. 8
Scatter plot between the predicted logPo/w and the experimental percent inhibition
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References

    1. Annunziata F, Pinna C, Dallavalle S, Tamborini L, Pinto A. Int J Mol Sci. 2020;21:4618–4626. doi: 10.3390/ijms21134618. - DOI - PMC - PubMed
    1. Arango V, Robledo S, Séon-Méniel B, Figadère B, Cardona W, Saez J, Otalvaro F. Coumarins from Galipea panamensis and their activity against Leishmania panamensis. J Nat Prod. 2010;73:1012–1019. doi: 10.1021/np100146y. - DOI - PubMed
    1. Arnold K, Bordoli L, Kopp J, Schwede T. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics. 2006;22:195–201. doi: 10.1093/bioinformatics/bti770. - DOI - PubMed
    1. Bienert S, Waterhouse A, de Beer TA, Tauriello G, Studer G, Bordoli L, Schwede T. The SWISS-MODEL repository-new features and functionality. Nucleic Acids Res. 2017;45:313–319. doi: 10.1093/nar/gkw1132. - DOI - PMC - PubMed
    1. Bowie JU, Luthy R, Eisenberg DA. method to identify protein sequences that fold into a known three-dimensional structure. Science. 1991;253:164–170. doi: 10.1126/science.1853201. - DOI - PubMed

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