Structure-based virtual screening for insect ecdysone receptor ligands using MM/PBSA.
Ecdysone receptor
Free energy calculation
MM/PBSA
Molecular dynamics
Virtual screening
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 03 2019
15 03 2019
Historique:
received:
13
11
2018
revised:
01
02
2019
accepted:
04
02
2019
pubmed:
17
2
2019
medline:
16
1
2020
entrez:
17
2
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30770256
pii: S0968-0896(18)31929-1
doi: 10.1016/j.bmc.2019.02.011
pii:
doi:
Substances chimiques
Insect Proteins
0
Insecticides
0
Ligands
0
Receptors, Steroid
0
ecdysone receptor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1065-1075Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.