Privileged Structures in GPCRs
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.
KeywordsBinding Pocket Inactive State Orphan Receptor Small Ligand Synthetic Ligand
G-protein coupled receptor
Transmembrane helix (in membrane proteins generally, here in GPCRs)
Amino acids are abbreviated with standard single letter code.
The GPCR database [www.gpcr.org/7tm] based at CMBI, Nijmegen, NL.
Nuclear magnetic resonance
- Mason JS, Morize I, Menard PR, Cheney DL, Hulme C, Labaudiniere RF (1999) New 4-point pharmacophore method for molecular similarity and diversity applications: overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures. J Med Chem 42:3251–3264CrossRefPubMedGoogle Scholar
- Nicolaou KC, Pfefferkorn JA, Barluenga S, Mitchell HJ, Roecker AJ, Cao GQ (2000a) Natural product-like combinatorial libraries based on privileged structures. The “libraries from libraries” principle for diversity enhancement of benzopyran libraries. J Am Chem Soc 122:9968–9976CrossRefGoogle Scholar
- Nicolaou KC, Pfefferkorn JA, Mitchell HJ, Roecker AJ, Barluenga S, Cao GQ, Affleck RL, Lillig JE (2000b) Natural product-like combinatorial libraries based on privileged structures. Construction of a 10000-membered benzopyran library by directed split-and-pool chemistry using nanokans and optical encoding. J Am Chem Soc 122:9954–9967CrossRefGoogle Scholar
- Pal D, Chakrabarti P (2001) Non-hydrogen bond interactions involving the methionine sulfur atom. J Biomolec Struct Dynamics 19:115–128Google Scholar
- Samanta U, Pal D, Chakrabarti P (1999) Packing of aromatic rings against tryptophan residues in proteins. Acta Crystallographica D55:1421–1427Google Scholar
- Van de Peer Y, De Wachter R (1997) Construction of evolutionary distance trees with TREECON for Windows: accounting for variation in nucleotide substitution rate among sites. Comput Appl Biosci 13:227–230Google Scholar