Hierarchical Virtual Screening of Potential Insectides Inhibitors of Acetylcholinesterase and Juvenile Hormone from Temephos

Abstract

Aedes aegypti (Linnaeus, 1762; Diptera: Culicidae) is the main vector transmitting viral diseases such as dengue fever, dengue haemorrhagic fever, urban yellow fever, zika and chikungunya. Worldwide, especially in the Americas and Brazil, many cases of dengue have been reported in recent years, which have shown significant growth. The main control strategy is the elimination of the vector, carried out through various education programs, to change human habits, but the most usual is biological control, together with environmental management and chemical control. The most commonly insecticide used is temephos (an organophosphorus compound), but Aedes aegypti populations have shown resistance and the product is highly toxic, so we chose it as a template molecule to perform a ligand-based virtual screening in the ChemBrigde (DIVERSet-CL subcollection) database, searching for derivatives with similarity in shape (ROCS) and electrostatic potential (EON). Thus, fourty-five molecules were filtered based on their pharmacokinetic and toxicological properties and 11 molecules were selected by a molecular docking study, including binding affinity and mode of interaction. The L46, L66 and L68 molecules show potential inhibitory activity for both the insect (−9.28, −10.08 and −6.78 Kcal/mol, respectively) and human (−6.05, 6.25 and 7.2 Kcal/mol respectively) enzymes, as well as the juvenile hormone protein (−9.2; −10.96 and −8.16 kcal/mol, respectively), showing a significant difference in comparison to the template molecule temephos. Molecules L46, L66 and L68 interacted with important amino acids at each catalytic site of the enzyme reported in the literature. Thus, the molecules here investigated are potential inhibitors for both the acetylcholinesterase enzymes and juvenile hormone protein–from insect and humans, characterizing them as a potential insecticide against the Aedes aegypti mosquito.

Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach

“…In the sequence, the selected compounds were submitted to electrostatic correlations of aligned molecules based on the Tanimoto electrostatic score in EON software [ 34 , 35 ]. This electrostatic potential is calculated using OpenEye’s Poisson-Boltzmann (PB) electrostatic calculation [ 33 , 36 ]. The Top 100 molecules by database (Top_100), led to six hundred structures (600) hits with best alignment based on the electrostatic potential [ 15 ].…”

Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites

“…Thus, it is clear that SBVS using the β-haematin crystal gives better hit rates than the LBVS method reported here. Nonetheless, the method has the strategic advantage of hopping from one drug-like molecular scaffold to another, allowing rapid discovery of new chemotypes and thus suggesting useful new hits for further exploration in drug discovery [46][47][48]. Indeed, the structures identified in this study with β-haematin inhibition and/or parasite killing activity might be of interest for future investigations.…”

Virtual Screening Approach to Identify High-Affinity Inhibitors of Serum and Glucocorticoid-Regulated Kinase 1 among Bioactive Natural Products: Combined Molecular Docking and Simulation Studies

“…The structure-activity relationship is the connection between the molecular structure of a compound and its biological activity, which has been utilized in structure-based drug designing to develop effective small molecules against a biological target [29]. There are two known SGK inhibitors, namely GSK650394 and EMD638683, which have effective characteristics to inhibit the activity of SGK1.…”