title: In Silico Investigation of the Neurotensin Receptor 1 Binding Site: Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist.
abstract: 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 neurological disorders and the promotion of cancer cells. Recently, a high-resolution x-ray crystal structure of NTSR1 in complex with NTS8-13 has been determined, providing novel insights into peptide ligand recognition by 7TM receptors. SR48692, a potent and selective small molecule antagonist has previously been used extensively as a tool compound to study NTSR1 receptor signaling properties. To investigate the binding mode of SR48692 and other small molecule compounds 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 observed, despite their distinct chemical nature and inverse pharmacological 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 molecule ligand binding to NTSR1 and could facilitate the structure-based design of non-peptide ligands for the evaluation of the pharmacological potential of NTSR1 in neurological disorders and cancer.
authors: M Lückmann, B Holst, TW Schwartz, TM Frimurer, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen. Denmark.
authors: Michael
authors: M
authors: Lückmann
authors: M Lückmann, B Holst, TW Schwartz, TM Frimurer, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen. Denmark.
authors: Birgitte
authors: B
authors: Holst
authors: M Lückmann, B Holst, TW Schwartz, TM Frimurer, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen. Denmark.
authors: Thue W
authors: TW
authors: Schwartz
authors: M Lückmann, B Holst, TW Schwartz, TM Frimurer, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen. Denmark. thomas.frimurer@cpr.ku.dk.|TM Frimurer, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen. Denmark. thomas.frimurer@cpr.ku.dk.
authors: Thomas M
authors: TM
authors: Frimurer
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009496:Neurotensin / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D000072417:Protein Domains; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D018028:Receptors, Neurotensin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008024:Ligands; D010455:Peptides; D011720:Pyrazoles; D011804:Quinolines; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; C079087:SR 48692; D009496:Neurotensin
keywords: Docking; Molecular modeling; Virtual screening