title: Molecular modeling of the second extracellular loop of G-protein coupled receptors and its implication on structure-based virtual screening.
abstract: The current study describes the validation of high-throughput modeling procedures for the construction of the second extracellular loop (ecl2) of all nonolfactory human G Protein-coupled receptors. Our modeling flowchart is based on the alignment of essential residues determining the particular ecl2 fold observed in the bovine rhodopsin (bRho) crystal structure. For a set of GPCR targets, the dopamine D2 receptor (DRD2), adenosine A3 receptor (AA3R), and the thromboxane A2 receptor (TA2R), the implications of including ecl2 atomic coordinates is evaluated in terms of structure-based virtual screening accuracy: the suitability of the 3D models to distinguish between known antagonists and randomly chosen decoys using automated docking approaches. The virtual screening results of different models describing increasingly exhaustive receptor representations (seven helices only, seven helices and ecl2 loop, full model) have been compared. Explicit modeling of the ecl2 loop was found to be important in only one of three test cases whereas a loopless model was shown to be accurate enough in the two other receptors. An exhaustive comparison of ecl2 loops of 365 receptors to that of bRho suggests that explicit ecl2 loop modeling should be reserved to receptors where loop building can be guided by experimental restraints.
authors.affiliation: Bioinformatics of the Drug, CNRS UMR 7175-LC1, Université Louis Pasteur Strasbourg I, Illkirch F-67401, France.
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Nicolas
authors.initials: N
authors.lastname: Foata
authors.forename: Ola
authors.initials: O
authors.lastname: Engkvist
authors.forename: Didier
authors.initials: D
authors.lastname: Rognan
mesh_terms: D058918:Adenosine A3 Receptor Antagonists; D000595:Amino Acid Sequence; D003198:Computer Simulation; D065127:Dopamine D2 Receptor Antagonists; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D046609:Libraries, Digital; D008024:Ligands; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D017448:Receptors, Dopamine D2 / Q000737:chemistry*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016415:Sequence Alignment
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D043684:Receptor, Adenosine A3; D017448:Receptors, Dopamine D2; D044244:Receptors, Thromboxane A2, Prostaglandin H2