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

Abstract

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.