3-styrylcoumarin scaffold-based derivatives as a new approach for leishmaniasis intervention: biological and molecular modeling studies
ABSTRACT: Seven 3-styryl coumarin was 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 r...
- Autores:
-
Yepes Pérez, Andrés Felipe
Robledo Restrepo, Sara María
Quintero Saumeth, Jorge Ricardo
Cardona Galeano, Wilson
- Tipo de recurso:
- Article of investigation
- Fecha de publicación:
- 2024
- Institución:
- Universidad de Antioquia
- Repositorio:
- Repositorio UdeA
- Idioma:
- eng
- OAI Identifier:
- oai:bibliotecadigital.udea.edu.co:10495/41180
- Acceso en línea:
- https://hdl.handle.net/10495/41180
- Palabra clave:
- Leishmaniasis
https://id.nlm.nih.gov/mesh/D007896
3-styrylcoumarins
Docking studies
Molecular modeling studies
In-silico pharmacokinetic evaluation
- Rights
- openAccess
- License
- https://creativecommons.org/licenses/by/4.0/
| Summary: | ABSTRACT: Seven 3-styryl coumarin was 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 a 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 afrm 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 amino acids are contributing strongly to ligand binding. Finally, an optimal pharmacokinetic profile was also estimated for 6. Altogether, coumarin 6 could be addressed as a starting point for further pharmacological studies concerning the therapeutic leishmaniasis intervention. |
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