In Silico Investigation of the Neurotensin Receptor 1 Binding Site: Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist

Publikation: Bidrag til tidsskriftLetterForskningfagfællebedømt

The neurotensin receptor 1 (NTSR1) belongs to the family of 7TM, G protein-coupled receptors, and is activated by the 13-amino-acid peptide neurotensin (NTS) that has been shown to play important roles in neurol. disorders and the promotion of cancer cells. Recently, a high-resoln. x-ray crystal structure of NTSR1 in complex with NTS8-13 has been detd., providing novel insights into peptide ligand recognition by 7TM receptors. SR48692, a potent and selective small mol. antagonist has previously been used extensively as a tool compd. to study NTSR1 receptor signaling properties. To investigate the binding mode of SR48692 and other small mol. compds. to NTSR1, we applied an Automated Ligand-guided Backbone Ensemble Receptor Optimization protocol (ALiBERO), taking receptor flexibility and ligand knowledge into account. Structurally overlapping binding poses for SR48692 and NTS8-13 were obsd., despite their distinct chem. nature and inverse pharmacol. profiles. The optimized models showed significantly improved ligand recognition in a large-scale virtual screening assessment compared to the crystal structure. Our models provide new insights into small mol. ligand binding to NTSR1 and could facilitate the structure-based design of non-peptide ligands for the evaluation of the pharmacol. potential of NTSR1 in neurol. disorders and cancer. [on SciFinder(R)]
TidsskriftMolecular Informatics
Sider (fra-til)19-24
Antal sider6
StatusUdgivet - 2016

ID: 150703337