Molecular modeling aided design of nicotinic acid receptor GPR109A agonists

Bioorg Med Chem Lett. 2008 Sep 15;18(18):4963-7. doi: 10.1016/j.bmcl.2008.08.030. Epub 2008 Aug 14.


A homology model of the nicotinic acid receptor GPR109A was constructed based on the X-ray crystal structure of bovine rhodopsin. An HTS hit was docked into the homology model. Characterization of the binding pocket by a grid-based surface calculation of the docking model suggested that a larger hydrophobic body plus a polar tail would improve interaction between the ligand and the receptor. The designed compounds were synthesized, and showed significantly improved binding affinity and activation of GPR109A.

MeSH terms

  • Binding Sites
  • Combinatorial Chemistry Techniques
  • Humans
  • Models, Molecular*
  • Molecular Structure
  • Niacin / metabolism
  • Nicotinic Agonists / chemical synthesis*
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, Nicotinic
  • Structure-Activity Relationship
  • ortho-Aminobenzoates / chemical synthesis*
  • ortho-Aminobenzoates / chemistry
  • ortho-Aminobenzoates / pharmacology*


  • HCAR2 protein, human
  • HCAR3 protein, human
  • Nicotinic Agonists
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • ortho-Aminobenzoates
  • Niacin