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 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.

• 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/