Identification of Potential Inhibitors from Pyriproxyfen with Insecticidal Activity by Virtual Screening

Abstract

Aedes aegypti is the main vector of dengue fever transmission, yellow fever, Zika, and chikungunya in tropical and subtropical regions and it is considered to cause health risks to millions of people in the world. In this study, we search to obtain new molecules with insecticidal potential against Ae. aegypti via virtual screening. Pyriproxyfen was chosen as a template compound to search molecules in the database Zinc_Natural_Stock (ZNSt) with structural similarity using ROCS (rapid overlay of chemical structures) and EON (electrostatic similarity) software, and in the final search, the top 100 were selected. Subsequently, in silico pharmacokinetic and toxicological properties were determined resulting in a total of 14 molecules, and these were submitted to the PASS online server for the prediction of biological insecticide and acetylcholinesterase activities, and only two selected molecules followed for the molecular docking study to evaluate the binding free energy and interaction mode. After these procedures were performed, toxicity risk assessment such as LD50 values in mg/kg and toxicity class using the PROTOX online server, were undertaken. Molecule ZINC00001624 presented potential for inhibition for the acetylcholinesterase enzyme (insect and human) with a binding affinity value of −10.5 and −10.3 kcal/mol, respectively. The interaction with the juvenile hormone was −11.4 kcal/mol for the molecule ZINC00001021. Molecules ZINC00001021 and ZINC00001624 had excellent predictions in all the steps of the study and may be indicated as the most promising molecules resulting from the virtual screening of new insecticidal agents.

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

“…Figure 6 shows the poses calculated in relation to the deposited PDB complexes, with the deviation of the mean square root (RMSD) calculated at 0.91 Å for rofecoxib (RCX; 5KIR PDB code), 0.63 Å for celecoxib ( CEL ; 3LN1 PDB code) and 0.71 Å for indomethacin ( IMS ; 2YOE PDB code). Such a methodology provides alignment values for a maximum of 2 Å for the study of molecular docking, and accordingly, it validates the protocols used [ 25 , 26 ].…”

“…The validation protocol was based on the determination of the x, y, and z coordinates according to the average region of the active site; these values are observed in Table 16 . The energy function score was used to evaluate the free binding energy (ΔG) of the interaction of the receptors with the ligands [ 25 ].…”

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

“…The parameters used for screening were established in the QikProp environment, and thus previously selected for using the Derek software, for searching molecules in the database with potential biocidal effect, in particular for Aedes aegypti , and not active against any other organism or the environment. Parameters were used to evaluate if the molecule can overcome the barriers and reach the CNS (Central Nervous System), so that the “star” parameter or drug-like properties were analyzed, which are compared with 95% commercial and common drugs [23]; MW, corresponding to the molecular weight of the molecule in (g·mol −1 ), ClogP/w, which corresponds to the octanol and water partition coefficient; HBD means hydrogen bonds that would be donated to the water solvent; HBA means the number of hydrogen bonds that would be accepted from a solvent [24,25,26,27,28]. The temephos molecule and those selected from the database were within the recommended values regarding the drug-like as well as the physicochemical properties, in order to show potential CNS action.…”

“…The crystallographic structure of acetylcholinesterase (AChE) from Drosophila melanogaster in complex with with tacrine [(9-3-iodobenzylamino)-1,2,3,4-tetrahydroacridine] (I40) was used, solved by X-ray diffraction and resolution of 2.7 Å [53]. The crystallographic structure of the recombinant human acetylcholinesterase (hAChE) complexed with (–)-galantamine (GNT), solved by X-ray diffraction and resolution of 2,4 Å [27] was also used. The crystallographic structure of juvenile hormone (PDB ID 5V13), in complex with (2E,6E)-9-[(2R)-3,3-dimethyloxiran-2-yl]-3,7-dimethylnona-2,6-methylene dienoate, (JHIII), with resolution of 1.87 Å [16] was also used.…”

Identification of New Inhibitors with Potential Antitumor Activity from Polypeptide Structures via Hierarchical Virtual Screening

“…The values of Pa and Pi are independent, ranging from 0 to 1. The biological activity spectra were predicted for the compounds from the virtual screening with the web server PASS (Prediction of Activity Spectra for Substances) web server [37] and according to studies developed by Ferreira et al and Ramos et al [49,50].…”