Triagem virtual de selenoetilenolacticamidas e narilpropanamidas com potencial atividade antileishmania

Abstract

Neglected tropical diseases are characterized as a group of 17 communicable diseases, caused by parasitic agents that prevail in regions of tropical and subtropical climate and reach estimates of 500 thousand cases per year. Leishmaniasis is an infectious pathology caused by protozoa of the genus Leishmania sp belonging to the Trypanosomatidae family. The drugs available for treatment have many related drawbacks. Possible therapeutic alternatives include organoselenium compounds, since selenium represents an essential trace element in the biological functions and nutrition of living beings, and to date, countless activities and applications of these bioactive agents have been reported. As alternatives for obtaining the results, the Computer Aided Drug Designer (CADD) Development Methods are mentioned, which represent fast, effective and affordable alternatives that guarantee greater targeting and practicality. to the developed study. In this perspective, the present study aimed to perform the virtual screening of synthetic derivatives of selenoethylenolacticamides as potential activities for the protozoa Leishmania infantum and Leishmania amazonensis. To obtain the results, 8 prediction models were elaborated regarding the amstigote and promastigote forms of the organisms under study. The data sets were obtained from the ChEMBL database, the compounds being classified according to the pIC50 values, to generate and validate the model using the Random Forest algorithm, in addition, a consensus analysis was performed between the models analyzed. Molecular docking simulations were performed using the Molegro Virtual Docking software and two proteins obtained from the Protein Data Bank were used and the remaining six were built by homology. In addition, a simple pharmacophoric study with principal component analyzes (PCA) and consensus (CPCA), finally, parameters related to bioavailability such as oral absorption and violations of the Lipinski rule were evaluated, in addition to toxicity assessments, and the most likely molecules were selected for organic synthesis. The consensus models developed, with the exception of the model for the amastigote form of L. amazonensis, allowed the classification of molecules with probabilities above 60%, corresponding respectively to L. infantum in the selection of 22 molecules for the amastigote form, for the form promastigote the number corresponded to 28 compounds, and for L. amazonensis the number corresponded to 26 molecules. The molecular docking analyzes performed were favorable, demonstrating that the selected compounds interacted with the selected enzymes, since all of them presented negative energies, and for L. infantum the molecules 27 and 28 showed multitarget potential, as they obtained lower energies than the ligands. The analyzes of CPCA and PCA identified that the most representative groups of descriptors correspond to OH2 and LOGS, these descriptors are related to water solubility. Regarding absorption, this was higher than 60% indicating that the compounds have high rates of oral absorption, as well as a good availability, since in most compounds only one violation of the rule was registered. In the toxicity assessment, only seven compounds showed signs of toxicity in up to one or two parameters. The methodology used was effective and showed good reproducibility, since it allowed the selection of 16 compounds that were synthesized and are under biological testing.