Structure-based virtual screening for insect ecdysone receptor ligands using MM/PBSA. Issue 6 (15th March 2019)

• Record Type: Journal Article
• Authors: Horoiwa, Shinri; Yokoi, Taiyo; Masumoto, Satoru; Minami, Saki; Ishizuka, Chiharu; Kishikawa, Hidetoshi; Ozaki, Shunsuke; Kitsuda, Shigeki; Nakagawa, Yoshiaki; Miyagawa, Hisashi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 6(2019)
• Page Start: 1065
• Page End: 1075
• Publication Date: 2019-03-15
• Subjects: Ecdysone receptor -- Free energy calculation -- MM/PBSA -- Molecular dynamics -- Virtual screening; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.02.011
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The ecdysone receptor (EcR) is an insect nuclear receptor that is activated by the molting hormone, 20-hydroxyecdysone. Because synthetic EcR ligands disrupt the normal growth of insects, they are attractive candidates for new insecticides. In this study, the Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method was used to predict the binding activity of EcR ligands. Validity analyses using 40 known EcR ligands showed that the binding activity was satisfactorily predicted when the ligand conformational free energy term was introduced. Subsequently, this MM/PBSA method was applied to structure-based hierarchical virtual screening, and 12 candidate compounds were selected from a database of 3.8 million compounds. Five of these compounds were active in a cell-based competitive binding assay. The most potent compound is a simple proline derivative with low micromolar binding activity, representing a valuable lead compound for further structural optimization.