Human Serotonin 5-HT2CG Protein-Coupled Receptor Homology Model from theβ2Adrenoceptor Structure: Ligand Docking and Mutagenesis Studies.
Activation of the serotonin (5-hydroxytryptamine, 5-HT) 5HT2CG protein-coupled receptor (GPCR) is proposed as novel pharmacotherapy for obesity and neuropsychiatric disorders. In contrast, activation of the 5-HT2Aand 5-HT2BGPCRs is associated with untoward hallucinogenic and cardiopulmonary effects, respectively. There is no crystal structure available to guide design of 5-HT2Creceptor-specific ligands. For this reason, a homology model of the 5-HT2Creceptor was built based on the crystal structure of the humanβ2adrenoceptor GPCR to delineate molecular determinants of ligand-receptor interactions for drug design purposes. Computational and experimental studies were carried out to validate the model. Binding of N(CH3)2-PAT [(1R, 3S)-(-)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene], a novel 5-HT2Cagonist/5-HT2A/2Binverse agonist, and its secondary [NH(CH3)-PAT] and primary (NH2-PAT) amine analogs were studied at the 5-HT2Cwild type (WT) and D3.32A, S3.36A, and Y7.43A 5-HT2Cpoint-mutated receptors. Reference ligands included the tertiary amines lisuride and mesulergine and the primary amine 5-HT. Modeling results indicated that 5-HT2Cresidues D3.32, S3.36, and Y7.43 play a role in ligand binding. Experimental ligand binding results with WT and point-mutated receptors confirmed the impact of D3.32, S3.36, and Y7.43 on ligand affinity.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610.
Tania Có
TC
Rdova-Sintjago
Nancy
N
Villa
Clinton
C
Canal
Raymond
R
Booth
GPCR homology modeling; drug design; serotonin 5-HT2C receptor