Candidatos a fármacos contra leishmaniose: Compreensão da relação estrutura molecular com a atividade biológica e desenho racional de inibidores

Abstract

The development of a new drug can take many years and several computational approaches which were used at different stages of the process in order to improve the discovery of new compounds to treat several pathologies, including leishmaniasis, a neglected disease who needs of effective drugs, with low toxicity and cost. Thereby, a review on the literature searching form compounds with inhibitory activity on topoisomerase and arginase (targets related to leishmaniasis), was carried out, and so it was possible to verify what are the main structural features responsible for the interactions with these receptors. For topoisomerase, the aromaticity of the ligands improve their affinity for the enzyme, mainly by increasing the possibilities of these compounds that may act in the intercalation of the DNA strand break, since topoisomerase venoms that act as intercalating like camptothecin, show high affinity values of -9.87 kcal/mol. In the arginase target, a model of homology (Leishmania amazonensis) was generated according to the parameters used in the SWISS-MODEL platform, that is reliable and suitable for use in molecular docking, according to the parameters QMEAN and GMQE with respective values -0.09 and 0.98. Furthermore, in arginase there is a predominance of interactions with cofactors (Mn2+) which are essential for the activity of the enzime, thus the inhibition presented by the caffeic acid with an affinity value of -11.56 kcal/cal, is a great exemplo. This kind of interaction was also observed in the virtual screening performed with the compounds from NuBBE database, with the molecules interacting with arginase through the cofactors, with the carboxylic acid function being predominant. Based on in silico results, six derivatives of caffeic acid were designed, of which the compound IV show better affinity for the parasite's arginase and it was synthesized in 35% yield. Further, compound IV was evaluated against L. amazonenses and L. infantum, and presented IC50 values of 0,25 e 0,35 μmol/L, respectively. These values shows that IV is a promising compound in the development of new candidates for drugs to treat leishmaniois, since the cytotoxicity assay performed on HepG2 cells showed a CC50 of 2,00 μmol/L. In this way, the present work contributes significantly to the development of new alternatives for the treatment of leishmaniasis.