Molting hormones can be mediated by a heterodimeric protein complex composed of the ecdysone receptor (EcR) and the ultraspiracle(USP). Up to now, six x-ray structures of the ligand-binding domains (LBDs) in EcRs from lepidopteran and dipteran insects, co-crystallized with the steroid hormone and the DBHs were published. Interestingly, the binding pockets for ecdysteroidsand DBHs were different on the partial overlaps, which meant the ligand-binding pockets of EcRs had a great structural adaptability. In the study, a database of 202,919 compounds was virtually screened by the quantitative and qualitative tools, and we focused on the common properties of steroidal and nonsteroidal ecdysone agonists to search new ligands. Firstly, two pharmacophore models were built, which had the common and critical features for steroid hormone and the DBHs. The true positive rate of both pharmacophore models are 100%. Then structural cluster and pesticide-like analysis were performed. And the rest of 2538 compounds were docked into EcRs. During the docking analysis, the enrichment curve of different scoring function was used to improve efficiency. Using the combination of Affinity dG, Alpha HB and ASE in MOE software, the first 32% of these compounds are positive. In order to increase the accuracy of the screening, we used QSAR models to evaluate the possibility of the potential ligands. The prediction accuracies of the QSAR model were 87.8% for the test set and 44.8% for the external validation set, respectively. Then we found 28 structurally diverse compounds, which had the good docking scores and high predicted pEC50 values. The vivo and vitro bioassay experiments are under investigation.

Virtual screening for potential ligands of insect ecdysone receptors

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.