title: GPCR antitarget modeling: pharmacophore models for biogenic amine binding GPCRs to avoid GPCR-mediated side effects.
abstract: G protein-coupled receptors (GPCRs) form a large protein family that plays an important role in many physiological and pathophysiological processes. However, the central role that the biogenic amine binding GPCRs and their ligands play in cell signaling poses a risk in new drug candidates that reveal side affinities towards these receptor sites. These candidates have the potential to interfere with the physiological signaling processes and to cause undesired effects in preclinical or clinical studies. Here, we present 3D cross-chemotype pharmacophore models for three biogenic amine antitargets: the alpha(1A) adrenergic, the 5-HT(2A) serotonin, and the D2 dopamine receptors. These pharmacophores describe the key chemical features present within these biogenic amine antagonists and rationalize the biogenic amine side affinities found for numerous new drug candidates. First applications of the alpha(1A) adrenergic receptor model reveal that these in silico tools can be used to guide the chemical optimization towards development candidates with fewer alpha(1A)-mediated side effects (for example, orthostatic hypotension) and, thus, with an improved clinical safety profile.
authors.affiliation: Aventis Pharma Deutschland GmbH, A Company of the Sanofi-Aventis Group, Scientific and Medical Affairs, Drug Design, Industriepark Hoechst, Building G878, 65926 Frankfurt am Main, Germany. thomas.klabunde@aventis.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Klabunde
authors.forename: Andreas
authors.initials: A
authors.lastname: Evers
mesh_terms: D018674:Adrenergic Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001679:Biogenic Amines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019295:Computational Biology; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015203:Reproducibility of Results; D012702:Serotonin Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018674:Adrenergic Antagonists; D001679:Biogenic Amines; D043562:Receptors, G-Protein-Coupled; D012702:Serotonin Antagonists