title: Discovery of novel antagonists of human neurotensin receptor 1 on the basis of ligand and protein structure.
abstract: Neurotensin receptor 1 (NTR1) is a cell surface receptor belonging to the G protein-coupled receptor (GPCR) A superfamily. NTR1 plays an important role in neuronal and non-neuronal systems. Using the previously identified crystal structure of rat NTR1 (rNTR1), we screened for potential candidates of human NTR1 (hNTR1) ligand. Approximately 10,000 compounds were selected using the docking score, followed by pharmacophore-based virtual screening and a two-dimensional (2D)-fingerprint structural similarity search. The identified molecules were tested by in vitro calcium flux assay. Four compounds showed micromolar level affinity, of which, one compound can inhibit hNTR1/CHO cells' proliferation by cell viability assays. To improve the affinity of these positive hit compounds, a homology model of hNTR1 was built on the basis of the crystal structure of rNTR1. The hit compounds will be further optimized on the basis of the structure of the hNTR1 receptor to be the targets for drugs directed against diseases associated with hNTR1. The results demonstrate that the method we used is valid, which will be treated as a useful tool to search for the agonists or antagonists of our interested target protein. Moreover, the compound we tested may provide a hopeful clue for treating the diseases related with hNTR1.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, China.
authors.forename: Dong-Ling
authors.initials: DL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, China. Electronic address: xufeng@nankai.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor
keywords: 2D-fingerprint; Ligand compounds; Molecular dynamics; Neurotensin receptor; Pharmacophore