Potential inhibitors of the enzyme acetylcholinesterase and juvenile hormone with insecticidal activity: study of the binding mode via docking and molecular dynamics simulations.

Models validation in QSAR, pharmacophore, docking and others can ensure the accuracy and reliability of future predictions in design and selection of molecules with biological activity. In this study, pyriproxyfen was used as a pivot/template to search the database of the Maybridge Database for potential inhibitors of the enzymes acetylcholinesterase and juvenile hormone as well. The initial virtual screening based on the 3D shape resulted in 2000 molecules with Tanimoto index ranging from 0.58 to 0.88. A new reclassification was performed on the overlapping of positive and negative charges, which resulted in 100 molecules with Tanimoto's electrostatic score ranging from 0.627 to 0.87. Using parameters related to absorption, distribution, metabolism and excretion and the pivot molecule, the molecules selected in the previous stage were evaluated regarding these criteria, and 21 were then selected. The pharmacokinetic and toxicological properties were considered and for 12 molecules, the DEREK software not fired any alert of toxicity, which were thus considered satisfactory for prediction of biological activity using the Web server PASS. In the molecular docking with insect acetylcholinesterase, the Maybridge3_002654 molecule had binding affinity of -11.1 kcal/mol, whereas in human acetylcholinesterase, the Maybridge4_001571molecule show in silico affinity of -10.2 kcal/mol, and in the juvenile hormone, the molecule MCULE-8839595892 show in silico affinity value of -11.6 kcal/mol. Subsequent long-trajectory molecular dynamics studies indicated considerable stability of the novel molecules compared to the controls.AbbreviationsQSARquantitative structure-activity relationshipsPASSprediction of activity spectra for substancesCommunicated by Ramaswamy H. Sarma.