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.
Systematic residue numbering convention: GPCRs are of varying sizes, anywhere between approximately 315 and approximately 620 residues in length. This clearly poses problems for the creation of a standard numbering scheme for comparing residue positions across families. However, the length of the TM segments is more or less constant, and each TM has a pattern of conserved residues. Various schemes have been devised to pivot the numbering system about the most conserved residue in each TM. The GPCRDB system is just one of these. In this work, the residue numbers will take the form: (TM number)_(Position in that TM from the N-terminal end). Conversion to other standard numbering conventions can be made by consulting Bywater (2005) or Bondensgaard et al. (2004).
Orientation convention: Unlike molecules of water-soluble proteins, which are oriented either in the frame of the user's 3D graphics device or with the orientation that they had in the crystal lattice, membrane proteins should be considered in relation to their orientation relative to the membrane, usually this is horizontal (in the , plane). In the convention employed here, the cytosolic side of the membrane is placed below the membrane bilayer and the extracellular side above. Directional prepositions used in the text, “up” and “down”, “deeper down” etc. (i.e. along the z axis), are defined according to this convention.
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- 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
References
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 16:1130–1133
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 47:888–899
Burley SK, Petsko GA (1985) Aromatic-aromatic interaction: a mechanism of protein structure stabilisation. Science 229:23–28
Bywater RP (2005) Location and nature of the residues important for ligand recognition in Class A G-Protein coupled receptors. J Mol Recogn 18:60–72
Costantino L, Barlocco D (2006) Privileged structures as leads in medicinal chemistry. Curr Med Chem 13:65–85
DeSimone RW, Currie KS, Mitchell SA, Darrow JW, Pippin DA (2004) Privileged structures: applications in drug discovery. Comb Chem High Throughput Screen 7:473–494
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 13:3793–3796
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 15:4459–4462
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 40:1315–1324
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 56:67–84
Guo T, Hobbs DW (2003) Privileged structure-based combinatorial libraries targeting G protein-coupled receptors. Assay Drug Dev Technol 1:579–592
IUPAC (1999) Glossary of terms used in combinatorial chemistry. Pure Appl Chem 71:2349–2365
Jacoby E (2002) A novel chemogenomics knowledge-based ligand design strategy--application to G-protein coupled receptors. Quant Struct Activity Relat 20:115–122
Krieger E, Vriend G (2002) Models@Home: distributed computing in bioinformatics using a screensaver-based approach. Bioinformatics 18:315–318
Li J, Edwards PC, Burghammer M, Villa C, Schertler GF (2004) Structure of bovine rhodopsin in a trigonal crystal form. J Mol Biol 343:1409–1438
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 42:3251–3264
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 124:4832–4837
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 122:9968–9976
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 122:9954–9967
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 122:9939–9953
Nieto MJ, Philip AE, Poupaert JH, McCurdy CR (2005) Solution-phase parallel synthesis of spirohydantoins. J Comb Chem 7:258–263
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 52:553–560
Pal D, Chakrabarti P (2001) Non-hydrogen bond interactions involving the methionine sulfur atom. J Biomolec Struct Dynamics 19:115–128
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 289:739–745
Ruprecht JJ, Mielke T, Vogel R, Villa C, Schertler GFX (2004) Electron crystallography reveals the structure of metarhodopsin I. EMBO J 23:3609–3620
Samanta U, Pal D, Chakrabarti P (1999) Packing of aromatic rings against tryptophan residues in proteins. Acta Crystallographica D55:1421–1427
Samanta U, Pal D, Chakrabarti P (2000) Environment of tryptophan side chains in proteins. Proteins 38:288–300
Singh J, Thornton JM (1985) The interactions between phenylalanine rings in proteins. FEBS Lett 191:1–6
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 84:4384–4388
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 264:13572–13578
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 55:145–52
Suryanarayana S, von Zastrow M, Kobilka BK (1992) Identification of intramolecular interactions in adrenergic receptors. J Biol Chem 267:21991–21994
Thomas A, Meurisse R, Charloteaux B, Brasseur R (2002) Aromtaic side-chain interactions in proteins. Proteins 48:628–634
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 13:227–230
Vriend G (1990) WHAT IF: a molecular modelling and drug design program. J Mol Graph 8:52–56
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Bywater, R.P. (2007). Privileged Structures in GPCRs. In: Bourne, H., Horuk, R., Kuhnke, J., Michel, H. (eds) GPCRs: From Deorphanization to Lead Structure Identification. Ernst Schering Foundation Symposium Proceedings, vol 2006/2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/2789_2006_004
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DOI: https://doi.org/10.1007/2789_2006_004
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