Ligand Discovery From a Dopamine D3 Receptor Homology Model and Crystal Structure

Nat Chem Biol. 2011 Sep 18;7(11):769-78. doi: 10.1038/nchembio.662.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Combinatorial Chemistry Techniques
  • Dopamine Antagonists / chemistry
  • Dopamine Antagonists / pharmacology*
  • Ligands
  • Models, Chemical
  • Molecular Structure
  • Protein Binding
  • Receptors, Dopamine D3 / chemistry*
  • Receptors, Dopamine D3 / genetics
  • Receptors, Dopamine D3 / metabolism*
  • Small Molecule Libraries

Substances

  • Dopamine Antagonists
  • Ligands
  • Receptors, Dopamine D3
  • Small Molecule Libraries

Associated data

  • PubChem-Substance/125092008
  • PubChem-Substance/125092009
  • PubChem-Substance/125092010
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