title: Mutation-Guided Unbiased Modeling of the Fat Sensor GPR119 for High-Yield Agonist Screening.
abstract: Recent benchmark studies have demonstrated the difficulties in obtaining accurate predictions of ligand binding conformations to comparative models of G-protein-coupled receptors. We have developed a data-driven optimization protocol, which integrates mutational data and structural information from multiple X-ray receptor structures in combination with a fully flexible ligand docking protocol to determine the binding conformation of AR231453, a small-molecule agonist, in the GPR119 receptor. Resulting models converge to one conformation that explains the majority of data from mutation studies and is consistent with the structure-activity relationship for a large number of AR231453 analogs. Another key property of the refined models is their success in separating active ligands from decoys in a large-scale virtual screening. These results demonstrate that mutation-guided receptor modeling can provide predictions of practical value for describing receptor-ligand interactions and drug discovery.
authors.affiliation: NNF Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark; NNF Center for Protein Research, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Norn
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark; NNF Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Hauge
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark; NNF Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark; Danish Diabetes Academy, Sdr Boulevard 29, Odense C 5000, Denmark.
authors.forename: Maja S
authors.initials: MS
authors.lastname: Engelstoft
authors.affiliation: Medicinal Chemistry Department, Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Medicinal Chemistry Department, Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Juerg
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Medicinal Chemistry Department, Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark; NNF Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.affiliation: NNF Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark; NNF Center for Protein Research, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark. Electronic address: thomas.frimurer@cpr.ku.dk.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D055808:Drug Discovery / Q000379:methods; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D010069:Oxadiazoles / Q000494:pharmacology; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000235:genetics
chemical_list: C521085:AR 231453; C519854:GPR119 protein, human; D010069:Oxadiazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled