Abstract
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
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Binding Sites
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Combinatorial Chemistry Techniques
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Humans
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Models, Molecular*
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Molecular Structure
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Niacin / metabolism
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Nicotinic Agonists / chemical synthesis*
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Nicotinic Agonists / chemistry
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Nicotinic Agonists / pharmacology*
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Receptors, G-Protein-Coupled / agonists*
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Receptors, Nicotinic
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Structure-Activity Relationship
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ortho-Aminobenzoates / chemical synthesis*
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ortho-Aminobenzoates / chemistry
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ortho-Aminobenzoates / pharmacology*
Substances
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HCAR2 protein, human
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HCAR3 protein, human
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Nicotinic Agonists
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Receptors, G-Protein-Coupled
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Receptors, Nicotinic
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ortho-Aminobenzoates
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Niacin