Privileged Structures in GPCRs

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


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.


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.



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 [] based at CMBI, Nijmegen, NL.


X-ray crystallography


Nuclear magnetic resonance


  1. Bakshi RK, Hong Q, Tang R, Kalyani RN, Macneil T, Weinberg DH, Van der Ploeg LH, Patchett AA, Nargund RP (2006) Optimization of a privileged structure leading to potent and selective human melanocortin subtype--4 receptor ligands. Bioorg Med Chem Lett 16:1130–1133CrossRefPubMedGoogle Scholar
  2. Bondensgaard K, Ankersen M, Thogersen H, Hansen BS, Wulff BS, Bywater RP (2004) Recognition of privileged structures by G-protein coupled receptors. J Med Chem 47:888–899CrossRefPubMedGoogle Scholar
  3. Burley SK, Petsko GA (1985) Aromatic-aromatic interaction: a mechanism of protein structure stabilisation. Science 229:23–28CrossRefPubMedGoogle Scholar
  4. Bywater RP (2005) Location and nature of the residues important for ligand recognition in Class A G-Protein coupled receptors. J Mol Recogn 18:60–72CrossRefGoogle Scholar
  5. Costantino L, Barlocco D (2006) Privileged structures as leads in medicinal chemistry. Curr Med Chem 13:65–85CrossRefPubMedGoogle Scholar
  6. DeSimone RW, Currie KS, Mitchell SA, Darrow JW, Pippin DA (2004) Privileged structures: applications in drug discovery. Comb Chem High Throughput Screen 7:473–494PubMedGoogle Scholar
  7. Dyck B, Parker J, Phillips T, Carter L, Murphy B, Summers R, Hermann J, Baker T, Cismowski M, Saunders J, Goodfellow V (2003) Aryl piperazine melanocortin MC4 receptor agonists. Bioorg Med Chem Lett 13:3793–3796CrossRefPubMedGoogle Scholar
  8. Fisher MJ, Backer RT, Husain S, Hsiung HM, Mullaney JT, O'Brian TP, Ornstein PL, Rothhaar RR, Zgombick JM, Briner K (2005) Privileged structure-based ligands for melanocortin receptors-tetrahydroquinolines, indoles, and aminotetralines. Bioorg Med Chem Lett 15:4459–4462CrossRefPubMedGoogle Scholar
  9. Frimurer TM, Bywater RP, Naerum L, Nørskov-Lauritsen L, Brunak S (2000) Discriminating “drug-like” from “non drug-like” molecules: improving the odds. J Chem Inf Comput Sci 40:1315–1324CrossRefPubMedGoogle Scholar
  10. Gouldson PR, Kidley N, Bywater RP, Psaroudakis G, Brooks HD, Diaz C, Shire D, Reynolds CA (2004) Towards the active conformations of rhodopsin and the β-2-adrenergic receptors. Proteins Struct Funct Genet Bioinformat 56:67–84CrossRefGoogle Scholar
  11. Guo T, Hobbs DW (2003) Privileged structure-based combinatorial libraries targeting G protein-coupled receptors. Assay Drug Dev Technol 1:579–592CrossRefPubMedGoogle Scholar
  12. IUPAC (1999) Glossary of terms used in combinatorial chemistry. Pure Appl Chem 71:2349–2365CrossRefGoogle Scholar
  13. Jacoby E (2002) A novel chemogenomics knowledge-based ligand design strategy--application to G-protein coupled receptors. Quant Struct Activity Relat 20:115–122CrossRefGoogle Scholar
  14. Krieger E, Vriend G (2002) Models@Home: distributed computing in bioinformatics using a screensaver-based approach. Bioinformatics 18:315–318CrossRefPubMedGoogle Scholar
  15. Li J, Edwards PC, Burghammer M, Villa C, Schertler GF (2004) Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol 343:1409–1438CrossRefPubMedGoogle Scholar
  16. 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
  17. Mo Y, Subramanian G, Gao J, Ferguson DM (2002) Cation-π interactions: an energy decomposition analysis and its implications in δ-opioid receptor-ligand binding. J Am Chem Soc 124:4832–4837CrossRefPubMedGoogle Scholar
  18. 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
  19. 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
  20. Nicolaou KC, Pfefferkorn JA, Roecker AJ, Cao GQ, Barluenga S, Mitchell HJ (2000c) Natural product-like combinatorial libraries based on privileged structures. General principles and solid-phase synthesis of benzopyrans. J Am Chem Soc 122:9939–9953CrossRefGoogle Scholar
  21. Nieto MJ, Philip AE, Poupaert JH, McCurdy CR (2005) Solution-phase parallel synthesis of spirohydantoins. J Comb Chem 7:258–263CrossRefPubMedGoogle Scholar
  22. Oliveira L, Paiva PB, Paiva AC, Vriend G (2003) Sequence analysis reveals how G protein-coupled receptors transduce the signal to the G protein. Proteins 52:553–560CrossRefPubMedGoogle Scholar
  23. Pal D, Chakrabarti P (2001) Non-hydrogen bond interactions involving the methionine sulfur atom. J Biomolec Struct Dynamics 19:115–128Google Scholar
  24. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289:739–745CrossRefPubMedGoogle Scholar
  25. Ruprecht JJ, Mielke T, Vogel R, Villa C, Schertler GFX (2004) Electron crystallography reveals the structure of metarhodopsin I. EMBO J 23:3609–3620CrossRefPubMedGoogle Scholar
  26. Samanta U, Pal D, Chakrabarti P (1999) Packing of aromatic rings against tryptophan residues in proteins. Acta Crystallographica D55:1421–1427Google Scholar
  27. Samanta U, Pal D, Chakrabarti P (2000) Environment of tryptophan side chains in proteins. Proteins 38:288–300CrossRefPubMedGoogle Scholar
  28. Singh J, Thornton JM (1985) The interactions between phenylalanine rings in proteins. FEBS Lett 191:1–6CrossRefGoogle Scholar
  29. Strader CD, Sigal IS, Register RB, Candelore MR, Rands E, Dixon RA (1987) Identification of residues required for ligand binding to the beta-adrenergic receptor. Proc Natl Acad Sci U S A 84:4384–4388CrossRefPubMedGoogle Scholar
  30. Strader CD, Candelore MR, Hill WS, Sigal IS, Dixon RA (1989) Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor. J Biol Chem 264:13572–13578PubMedGoogle Scholar
  31. Sukalovic V, Zlatovic M, Andric D, Roglic G, Kostic-Rajacic S, Soskic V (2005) Interaction of arylpiperazines with the dopamine receptor D2 binding site. Arzneimittelforschung 55:145–52PubMedGoogle Scholar
  32. Suryanarayana S, von Zastrow M, Kobilka BK (1992) Identification of intramolecular interactions in adrenergic receptors. J Biol Chem 267:21991–21994PubMedGoogle Scholar
  33. Thomas A, Meurisse R, Charloteaux B, Brasseur R (2002) Aromtaic side-chain interactions in proteins. Proteins 48:628–634CrossRefPubMedGoogle Scholar
  34. 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
  35. Vriend G (1990) WHAT IF: a molecular modelling and drug design program. J Mol Graph 8:52–56CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Magdalen CollegeOxfordEngland

Personalised recommendations