title: Ligand discovery from a dopamine D3 receptor homology model and crystal structure.
abstract: G protein-coupled receptors (GPCRs) are intensely studied as drug targets and for their role in signaling. With the determination of the first crystal structures, interest in structure-based ligand discovery increased. Unfortunately, for most GPCRs no experimental structures are available. The determination of the D(3) receptor structure and the challenge to the community to predict it enabled a fully prospective comparison of ligand discovery from a modeled structure versus that of the subsequently released crystal structure. Over 3.3 million molecules were docked against a homology model, and 26 of the highest ranking were tested for binding. Six had affinities ranging from 0.2 to 3.1 μM. Subsequently, the crystal structure was released and the docking screen repeated. Of the 25 compounds selected, five had affinities ranging from 0.3 to 3.0 μM. One of the new ligands from the homology model screen was optimized for affinity to 81 nM. The feasibility of docking screens against modeled GPCRs more generally is considered.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Carlsson
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Coleman
authors.forename: Vincent
authors.initials: V
authors.lastname: Setola
authors.forename: John J
authors.initials: JJ
authors.lastname: Irwin
authors.forename: Hao
authors.initials: H
authors.lastname: Fan
authors.forename: Avner
authors.initials: A
authors.lastname: Schlessinger
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
mesh_terms: D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D050637:Receptors, Dopamine D3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries
chemical_list: D018492:Dopamine Antagonists; D008024:Ligands; D050637:Receptors, Dopamine D3; D054852:Small Molecule Libraries