| Autor: |
Da Costa GV; Graduate Program in Network in Pharmaceutical Innovation, Federal University of Amapá, Macapá 68902-280, AP, Brazil.; Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil.; Laboratory of Biotechnology in Natural Products, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil., Neto MFA; Laboratory Molecular Modeling, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil., Da Silva AKP; Laboratory of Biotechnology in Natural Products, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil., De Sá EMF; Laboratory of Biotechnology in Natural Products, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil., Cancela LCF; Laboratory of Biotechnology in Natural Products, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil., Vega JS; Laboratory of Biotechnology in Natural Products, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil., Lobato CM; Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil.; Laboratory of Biotechnology in Natural Products, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil., Zuliani JP; Laboratory Cellular Immunology Applied to Health, Oswaldo Cruz Foundation, FIOCRUZ Rondônia, Porto Velho 78912-000, RO, Brazil., Espejo-Román JM; Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Institute of Biosanitary Research ibs, University of Granada, 18071 Granada, Spain., Campos JM; Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Institute of Biosanitary Research ibs, University of Granada, 18071 Granada, Spain., Leite FHA; Laboratory Molecular Modeling, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil., Santos CBR; Graduate Program in Network in Pharmaceutical Innovation, Federal University of Amapá, Macapá 68902-280, AP, Brazil.; Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil.; Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Institute of Biosanitary Research ibs, University of Granada, 18071 Granada, Spain. |
| Abstrakt: |
Aedes aegypti is the main vector that transmits viral diseases such as dengue, hemorrhagic dengue, urban yellow fever, zika, and chikungunya. Worldwide, many cases of dengue have been reported in recent years, showing significant growth. The best way to manage diseases transmitted by Aedes aegypti is to control the vector with insecticides, which have already been shown to be toxic to humans; moreover, insects have developed resistance. Thus, the development of new insecticides is considered an emergency. One way to achieve this goal is to apply computational methods based on ligands and target information. In this study, sixteen compounds with acceptable insecticidal activities, with 100% larvicidal activity at low concentrations (2.0 to 0.001 mg·L−1), were selected from the literature. These compounds were used to build up and validate pharmacophore models. Pharmacophore model 6 (AUC = 0.78; BEDROC = 0.6) was used to filter 4793 compounds from the subset of lead-like compounds from the ZINC database; 4142 compounds (dG < 0 kcal/mol) were then aligned to the active site of the juvenile hormone receptor Aedes aegypti (PDB: 5V13), 2240 compounds (LE < −0.40 kcal/mol) were prioritized for molecular docking from the construction of a chitin deacetylase model of Aedes aegypti by the homology modeling of the Bombyx mori species (PDB: 5ZNT), which aligned 1959 compounds (dG < 0 kcal/mol), and 20 compounds (LE < −0.4 kcal/mol) were predicted for pharmacokinetic and toxicological prediction in silico (Preadmet, SwissADMET, and eMolTox programs). Finally, the theoretical routes of compounds M01, M02, M03, M04, and M05 were proposed. Compounds M01−M05 were selected, showing significant differences in pharmacokinetic and toxicological parameters in relation to positive controls and interaction with catalytic residues among key protein sites reported in the literature. For this reason, the molecules investigated here are dual inhibitors of the enzymes chitin synthase and juvenile hormonal protein from insects and humans, characterizing them as potential insecticides against the Aedes aegypti mosquito. |
