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Privileged Structures in GPCRs

  • R. P. Bywater
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2006/2)

Abstract

Certain kinds of ligand substructures recur frequently in pharmacologically successful synthetic compounds. For this reason they are called privileged structures. In seeking an explanation for this phenomenon, it is observed that the privileged structure represents a generic substructure that matches commonly recurring conserved structural motifs in the target proteins, which may otherwise be quite diverse in sequence and function. Using sequence-handling tools, it is possible to identify which other receptors may respond to the ligand, as dictated on the one hand by the nature of the privileged substructure itself or by the rest of the ligand in which a more specific message resides. It is suggested that privileged structures interact with the partially exposed receptor machinery responsible for the switch between the active and inactive states. Depending on how they have been designed to interact, one can predispose these substructures to favour either one state or the other; thus privileged structures can be used to create either agonists or antagonists. In terms of the mechanism of recognition, the region that the privileged structures bind to are rich in aromatic residues, which explains the prevalence of aromatic groups and atoms such as sulphur or halogens in many of the ligands. Finally, the approach described here can be used to design drugs for orphan receptors whose function has not yet been established experimentally.

Keywords

Binding Pocket Inactive State Orphan Receptor Small Ligand Synthetic Ligand 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

GPCR

G-protein coupled receptor

TM

Transmembrane helix (in membrane proteins generally, here in GPCRs)

TM

Amino acids are abbreviated with standard single letter code.

GPCRDB

The GPCR database [www.gpcr.org/7tm] based at CMBI, Nijmegen, NL.

XRC

X-ray crystallography

NMR

Nuclear magnetic resonance

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Magdalen CollegeOxfordEngland

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