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 tidsskrift › Letter › Forskning › fagfællebedømt
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In Silico Investigation of the Neurotensin Receptor 1 Binding Site : Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist. / Lückmann, Michael; Holst, Birgitte; Schwartz, Thue W.; Frimurer, Thomas M.
I: Molecular Informatics, Bind 35, 2016, s. 19-24.Publikation: Bidrag til tidsskrift › Letter › Forskning › fagfællebedømt
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TY - JOUR
T1 - In Silico Investigation of the Neurotensin Receptor 1 Binding Site
T2 - Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist
AU - Lückmann, Michael
AU - Holst, Birgitte
AU - Schwartz, Thue W.
AU - Frimurer, Thomas M.
N1 - M1 - Copyright (C) 2015 American Chemical Society (ACS). All Rights Reserved. CAPLUS AN 2015:1496948(Journal)
PY - 2016
Y1 - 2016
N2 - 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)]
AB - 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)]
KW - SR48692 NTSR1 binding ligand neurol disorder cancer
U2 - 10.1002/minf.201500080
DO - 10.1002/minf.201500080
M3 - Letter
C2 - 27491650
VL - 35
SP - 19
EP - 24
JO - Molecular Informatics
JF - Molecular Informatics
SN - 1868-1743
ER -
ID: 150703337