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.
Int J Mol Sci. 2022 Jul 26;23(15):8218. doi: 10.3390/ijms23158218.
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.
埃及伊蚊是传播登革热、出血性登革热、城市型黄热病、寨卡和基孔肯雅热等病毒病的主要媒介。在世界范围内，近年来报告了许多登革热病例，且呈显著增长趋势。管理埃及伊蚊传播的疾病的最佳方法是用杀虫剂控制媒介，杀虫剂已经被证明对人类有毒，而且昆虫已经产生了抗药性。因此，开发新的杀虫剂被认为是当务之急。实现这一目标的一种方法是应用基于配体和靶标信息的计算方法。在这项研究中，从文献中选择了 16 种具有可接受杀虫活性的化合物，这些化合物在低浓度（2.0 至 0.001mg·L−1）下具有 100%的杀幼虫活性。这些化合物被用来建立和验证药效基团模型。药效基团模型 6（AUC = 0.78；BEDROC = 0.6）用于从 ZINC 数据库中的类先导化合物子集中筛选 4793 种化合物；然后将 4142 种化合物（dG < 0 kcal/mol）与埃及伊蚊保幼激素受体的活性位点对齐（PDB：5V13），从同源建模构建的埃及伊蚊几丁质脱乙酰酶模型中对 2240 种化合物（LE < -0.40 kcal/mol）进行优先分子对接（PDB：5ZNT），对齐了 1959 种化合物（dG < 0 kcal/mol），并对 20 种化合物（LE < -0.4 kcal/mol）进行了药代动力学和毒理学的预测（Preadmet、SwissADMET 和 eMolTox 程序）。最后，提出了化合物 M01、M02、M03、M04 和 M05 的理论途径。选择了化合物 M01−M05，与阳性对照相比，它们在药代动力学和毒理学参数方面表现出显著差异，并且与文献中报道的关键蛋白部位的催化残基相互作用。因此，这里研究的分子是昆虫和人类几丁质合酶和保幼激素蛋白的双重抑制剂，它们是针对埃及伊蚊的潜在杀虫剂。
