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Titolo:
Molecular modeling of the dopamine D-2 and serotonin 5-HT1A receptor binding modes of the enantiomers of 5-OMe-BPAT
Autore:
Homan, EJ; Wikstrom, HV; Grol, CJ;
Indirizzi:
Univ Groningen, Ctr Pharm, Dept Med Chem, NL-9713 AV Groningen, Netherlands Univ Groningen Groningen Netherlands NL-9713 AV V Groningen, Netherlands
Titolo Testata:
BIOORGANIC & MEDICINAL CHEMISTRY
fascicolo: 9, volume: 7, anno: 1999,
pagine: 1805 - 1820
SICI:
0968-0896(199909)7:9<1805:MMOTDD>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-COUPLED RECEPTORS; SITE-DIRECTED MUTAGENESIS; CONSERVED SERINE RESIDUES; MM3 FORCE-FIELD; ELECTRON CRYOMICROSCOPY; CONFORMATIONAL SPACE; 3-DIMENSIONAL MODELS; ANTIPSYCHOTIC AGENTS; LINKED RECEPTORS; LIGAND-BINDING;
Keywords:
molecular modeling; GPCR; dopamine; serotonin;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
83
Recensione:
Indirizzi per estratti:
Indirizzo: Homan, EJ Pharmacopeia Inc, CN 5350, Princeton, NJ 08543 USA Pharmacopeia Inc CN 5350 Princeton NJ USA 08543 on, NJ 08543 USA
Citazione:
E.J. Homan et al., "Molecular modeling of the dopamine D-2 and serotonin 5-HT1A receptor binding modes of the enantiomers of 5-OMe-BPAT", BIO MED CH, 7(9), 1999, pp. 1805-1820

Abstract

Molecular modeling studies were undertaken in order to elucidate the possible dopamine D-2 and serotonin 5-HT1A receptor binding modes of the enantiomers of 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-pylamino]tetralin (5-OMe-BPAT, 1). For this purpose, a combination of indirect molecular modeling and direct construction of the seven transmembrane (7TM) domains of the receptorswas employed in a stepwise, objective manner. Pharmacophore models and corresponding receptor maps were identified by superimposing selected sets of receptor agonists in their presumed pharmacologically active conformations,while taking the conformational freedom of the ligands into account. The 7TM models were then constructed around the agonist pharmacophore models, byadding the TM domains one-by-one. Initially, the relative positions of TM3, TM4, and TM5 were determined using the three-dimensional structure of bacteriorhodopsin, but subsequently the orientations of all TM domains were adjusted in order to mimic the topology of the TM domains of rhodopsin. The presumed dopamine D2 receptor binding conformations of(S)- and (R)-1 were determined by using the semirigid dopamine D2 receptor antagonist N-benzylpiquindone as a template for superposition. Similarly, the selective serotonin5-HT1A receptor agonist flesinoxan was employed for identifying the serotonin 5-HT1A receptor binding conformations of the enantiomers of 1. After docking of the presumed pharmacologically active conformations in the 7TM models and subsequent optimization of the binding sites, specific interactionsbetween the ligands and the surrounding amino acid residues, consistent with the structure-activity relationships, were observed. Thus, both enantiomers of 1 bound to the dopamine D-2 receptor model in a similar fashion: a reinforced electrostatic interaction was present between the protonated nitrogen atoms and Asp114 in TM3; their carbonyl groups accepted a H-bond from Ser121 in TM3; their amide NH groups acted as H-bond donor to Tyr416 in TM7; and their benzamide phenyl rings were involved in a hydrophobic edge-to-face interaction with Trp386 in TM6. Differences were observed in the orientations of the 2-aminotetralin moieties, which occupied the agonist binding site. Whereas the (S)-enantiomer could form a H-bond between its 5-methoxy substituent and Ser193 in TM5, the (R)-enantiomer could not, which may account for the differences in their intrinsic efficacies at the dopamine D-2 receptor. In the serotonin 5-HT1A receptor model, the benzamide phenyl ringsof both enantiomers were involved in hydrophobic face-to-face interactionswith Phe112 in TM3, while their protonated nitrogen atoms formed a reinforced electrostatic interaction with Asp116 in TM3. Consistent with the structure-affinity relationships of 1, the amide moieties were not involved in specific interactions. Both enantiomers of 1 could form a hydrogen bond between their 5-methoxy substituent and Thr200 in TM5, which may account for their full serotonin 5-HT1A receptor agonist properties. (C) 1999 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 07:37:14