{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T04:24:48Z","timestamp":1773289488564,"version":"3.50.1"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2010,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>G protein-coupled receptors (GPCRs) represent a family of well-characterized drug targets with significant therapeutic value. Phylogenetic classifications may help to understand the characteristics of individual GPCRs and their subtypes. Previous phylogenetic classifications were all based on the sequences of receptors, adding only minor information about the ligand binding properties of the receptors. In this work, we compare a sequence-based classification of receptors to a ligand-based classification of the same group of receptors, and evaluate the potential to use sequence relatedness as a predictor for ligand interactions thus aiding the quest for ligands of orphan receptors.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We present a classification of GPCRs that is purely based on their ligands, complementing sequence-based phylogenetic classifications of these receptors. Targets were hierarchically classified into phylogenetic trees, for both sequence space and ligand (substructure) space. The overall organization of the sequence-based tree and substructure-based tree was similar; in particular, the adenosine receptors cluster together as well as most peptide receptor subtypes (<jats:italic>e.g<\/jats:italic>. opioid, somatostatin) and adrenoceptor subtypes. In ligand space, the prostanoid and cannabinoid receptors are more distant from the other targets, whereas the tachykinin receptors, the oxytocin receptor, and serotonin receptors are closer to the other targets, which is indicative for ligand promiscuity. In 93% of the receptors studied, de-orphanization of a simulated orphan receptor using the ligands of related receptors performed better than random (AUC &gt; 0.5) and for 35% of receptors de-orphanization performance was good (AUC &gt; 0.7).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We constructed a phylogenetic classification of GPCRs that is solely based on the ligands of these receptors. The similarities and differences with traditional sequence-based classifications were investigated: our ligand-based classification uncovers relationships among GPCRs that are not apparent from the sequence-based classification. This will shed light on potential cross-reactivity of GPCR ligands and will aid the design of new ligands with the desired activity profiles. In addition, we linked the ligand-based classification with a ligand-focused sequence-based classification described in literature and proved the potential of this method for de-orphanization of GPCRs.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-11-316","type":"journal-article","created":{"date-parts":[[2010,6,10]],"date-time":"2010-06-10T18:59:03Z","timestamp":1276196343000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization"],"prefix":"10.1186","volume":"11","author":[{"given":"Eelke","family":"van der Horst","sequence":"first","affiliation":[]},{"given":"Julio E","family":"Peironcely","sequence":"additional","affiliation":[]},{"given":"Adriaan P","family":"IJzerman","sequence":"additional","affiliation":[]},{"given":"Margot W","family":"Beukers","sequence":"additional","affiliation":[]},{"given":"Jonathan R","family":"Lane","sequence":"additional","affiliation":[]},{"given":"Herman WT","family":"van Vlijmen","sequence":"additional","affiliation":[]},{"given":"Michael TM","family":"Emmerich","sequence":"additional","affiliation":[]},{"given":"Yasushi","family":"Okuno","sequence":"additional","affiliation":[]},{"given":"Andreas","family":"Bender","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2010,6,10]]},"reference":[{"issue":"6","key":"3773_CR1","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1124\/mol.63.6.1256","volume":"63","author":"R Fredriksson","year":"2003","unstructured":"Fredriksson R, Lagerstrom MC, Lundin L-G, Schioth HB: The G-Protein-Coupled Receptors in the Human Genome Form Five Main Families. Phylogenetic Analysis, Paralogon Groups, and Fingerprints. Molecular Pharmacology 2003, 63(6):1256\u20131272. 10.1124\/mol.63.6.1256","journal-title":"Molecular Pharmacology"},{"issue":"8","key":"3773_CR2","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1002\/cmdc.200600134","volume":"1","author":"E Jacoby","year":"2006","unstructured":"Jacoby E, Bouhelal R, Gerspacher M, Seuwen K: The 7 TM G-Protein-Coupled Receptor Target Family. Chem Med Chem 2006, 1(8):760\u2013782.","journal-title":"Chem Med Chem"},{"key":"3773_CR3","first-page":"1164772","volume-title":"Science","author":"V-P Jaakola","year":"2008","unstructured":"Jaakola V-P, Griffith MT, Hanson MA, Cherezov V, Chien EYT, Lane JR, IJzerman AP, Stevens RC: The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist. Science 2008, 1164772."},{"issue":"5","key":"3773_CR4","first-page":"561","volume":"4","author":"J Ballesteros","year":"2001","unstructured":"Ballesteros J, Palczewski K: G protein-coupled receptor drug discovery: Implications from the crystal structure of rhodopsin. Curr Opin Drug Discovery Dev 2001, 4(5):561\u2013574.","journal-title":"Curr Opin Drug Discovery Dev"},{"issue":"5854","key":"3773_CR5","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1126\/science.1150577","volume":"318","author":"V Cherezov","year":"2007","unstructured":"Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS, Choi H-J, Kuhn P, Weis WI, Kobilka BK, et al.: High-Resolution Crystal Structure of an Engineered Human \u03b22-Adrenergic G Protein Coupled Receptor. Science 2007, 318(5854):1258\u20131265. 10.1126\/science.1150577","journal-title":"Science"},{"issue":"7203","key":"3773_CR6","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nature07101","volume":"454","author":"T Warne","year":"2008","unstructured":"Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AGW, Tate CG, Schertler GFX: Structure of a \u03b21-adrenergic G-protein-coupled receptor. Nature 2008, 454(7203):486\u2013491. 10.1038\/nature07101","journal-title":"Nature"},{"issue":"10","key":"3773_CR7","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1002\/1439-7633(20021004)3:10<928::AID-CBIC928>3.0.CO;2-5","volume":"3","author":"T Klabunde","year":"2002","unstructured":"Klabunde T, Hessler G: Drug Design Strategies for Targeting G-Protein-Coupled Receptors. Chem Bio Chem 2002, 3(10):928\u2013944.","journal-title":"Chem Bio Chem"},{"issue":"6","key":"3773_CR8","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1021\/ci025538y","volume":"42","author":"KV Balakin","year":"2002","unstructured":"Balakin KV, Tkachenko SE, Lang SA, Okun I, Ivashchenko AA, Savchuk NP: Property-Based Design of GPCR-Targeted Library. J Chem Inf Comput Sci 2002, 42(6):1332\u20131342.","journal-title":"J Chem Inf Comput Sci"},{"issue":"26","key":"3773_CR9","doi-asserted-by":"publisher","first-page":"6529","DOI":"10.1021\/jm049448r","volume":"47","author":"LCW Chang","year":"2004","unstructured":"Chang LCW, Spanjersberg RF, von Frijtag Drabbe-K\u00fcnzel JK, Mulder-Krieger T, van den Hout G, Beukers MW, Brussee J, IJzerman AP: 2,4,6-Trisubstituted Pyrimidines as a New Class of Selective Adenosine A1Receptor Antagonists. J Med Chem 2004, 47(26):6529\u20136540. 10.1021\/jm049448r","journal-title":"J Med Chem"},{"key":"3773_CR10","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/2789_2006_004","volume-title":"GPCRs: From Deorphanization to Lead Structure Identification","author":"R Bywater","year":"2007","unstructured":"Bywater R: Privileged Structures in GPCRs. In GPCRs: From Deorphanization to Lead Structure Identification. Edited by: Bourne H, Horuk R, Kuhnke J, Michel H. Springer-Verlag; 2007:75\u201392. full_text"},{"issue":"3","key":"3773_CR11","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/sam.10046","volume":"2","author":"MR Doddareddy","year":"2009","unstructured":"Doddareddy MR, Westen GJPv, Horst Evd, Peironcely JE, Corthals F, IJzerman AP, Emmerich M, Jenkins JL, Bender A: Chemogenomics: Looking at biology through the lens of chemistry. Statistical Analysis and Data Mining 2009, 2(3):149\u2013160. 10.1002\/sam.10046","journal-title":"Statistical Analysis and Data Mining"},{"issue":"8","key":"3773_CR12","doi-asserted-by":"publisher","first-page":"719","DOI":"10.2174\/138620707782507313","volume":"10","author":"A Bender","year":"2007","unstructured":"Bender A, Young DW, Jenkins JL, Serrano M, Mikhailov D, Clemons PA, Davies JW: Chemogenomic data analysis: Prediction of small-molecule targets and the advent of biological fingerprints. Comb Chem High Throughput Screening 2007, 10(8):719\u2013731. 10.2174\/138620707782507313","journal-title":"Comb Chem High Throughput Screening"},{"issue":"1","key":"3773_CR13","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/sj.bjp.0707308","volume":"152","author":"T Klabunde","year":"2007","unstructured":"Klabunde T: Chemogenomic approaches to drug discovery: similar receptors bind similar ligands. Br J Pharmacol 2007, 152(1):5\u20137. 10.1038\/sj.bjp.0707308","journal-title":"Br J Pharmacol"},{"key":"3773_CR14","first-page":"1","volume":"2","author":"LFJ Kolakowski","year":"1994","unstructured":"Kolakowski LFJ: GCRDb: a G-protein-coupled receptor database. Recept Channels 1994, 2: 1\u20137.","journal-title":"Recept Channels"},{"issue":"2","key":"3773_CR15","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1002\/prot.20768","volume":"62","author":"J-S Surgand","year":"2006","unstructured":"Surgand J-S, Rodrigo J, Kellenberger E, Rognan D: A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors. Proteins: Struct, Funct, Bioinf 2006, 62(2):509\u2013538. 10.1002\/prot.20768","journal-title":"Proteins: Struct, Funct, Bioinf"},{"issue":"7168","key":"3773_CR16","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/nature06325","volume":"450","author":"SGF Rasmussen","year":"2007","unstructured":"Rasmussen SGF, Choi H-J, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VRP, Sanishvili R, Fischetti RF, et al.: Crystal structure of the human \u03b22adrenergic G-protein-coupled receptor. Nature 2007, 450(7168):383\u2013387. 10.1038\/nature06325","journal-title":"Nature"},{"issue":"14","key":"3773_CR17","doi-asserted-by":"publisher","first-page":"4429","DOI":"10.1021\/jm900319e","volume":"52","author":"DE Gloriam","year":"2009","unstructured":"Gloriam DE, Foord SM, Blaney FE, Garland SL: Definition of the G Protein-Coupled Receptor Transmembrane Bundle Binding Pocket and Calculation of Receptor Similarities for Drug Design. J Med Chem 2009, 52(14):4429\u20134442. 10.1021\/jm900319e","journal-title":"J Med Chem"},{"issue":"6","key":"3773_CR18","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1021\/ci600197y","volume":"46","author":"A Bender","year":"2006","unstructured":"Bender A, Jenkins JL, Glick M, Deng Z, Nettles JH, Davies JW: \"Bayes Affinity Fingerprints\" Improve Retrieval Rates in Virtual Screening and Define Orthogonal Bioactivity Space: When Are Multitarget Drugs a Feasible Concept? J Chem Inf Model 2006, 46(6):2445\u20132456. 10.1021\/ci600197y","journal-title":"J Chem Inf Model"},{"issue":"6","key":"3773_CR19","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1002\/cmdc.200700026","volume":"2","author":"A Bender","year":"2007","unstructured":"Bender A, Scheiber J, Glick M, Davies JW, Azzaoui K, Hamon J, Urban L, Whitebread S, Jenkins JL: Analysis of Pharmacology Data and the Prediction of Adverse Drug Reactions and Off-Target Effects from Chemical Structure. ChemMedChem 2007, 2(6):861\u2013873. 10.1002\/cmdc.200700026","journal-title":"ChemMedChem"},{"issue":"2","key":"3773_CR20","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nbt1284","volume":"25","author":"MJ Keiser","year":"2007","unstructured":"Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK: Relating protein pharmacology by ligand chemistry. Nat Biotech 2007, 25(2):197\u2013206. 10.1038\/nbt1284","journal-title":"Nat Biotech"},{"issue":"2","key":"3773_CR21","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1021\/ci8003896","volume":"49","author":"E van der Horst","year":"2009","unstructured":"van der Horst E, Okuno Y, Bender A, IJzerman AP: Substructure Mining of GPCR Ligands Reveals Activity-Class Specific Functional Groups in an Unbiased Manner. J Chem Inf Model 2009, 49(2):348\u2013360. 10.1021\/ci8003896","journal-title":"J Chem Inf Model"},{"key":"3773_CR22","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1109\/ICDM.2002.1183885","volume-title":"Proceedings of the 2002 IEEE International Conference on Data Mining: 2002","author":"C Borgelt","year":"2002","unstructured":"Borgelt C, Berthold MR: Mining Molecular Fragments: Finding Relevant Substructures of Molecules. In Proceedings of the 2002 IEEE International Conference on Data Mining: 2002. IEEE Computer Society; 2002:51\u201358. full_text"},{"key":"3773_CR23","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1145\/1014052.1014134","volume-title":"Proceedings of the tenth ACM SIGKDD international conference on Knowledge discovery and data mining: 2004","author":"S Nijssen","year":"2004","unstructured":"Nijssen S, Kok JN: A quickstart in frequent structure mining can make a difference. In Proceedings of the tenth ACM SIGKDD international conference on Knowledge discovery and data mining: 2004. ACM Press, New York, USA; 2004:647\u2013652. full_text"},{"issue":"2","key":"3773_CR24","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1124\/pr.57.2.5","volume":"57","author":"SM Foord","year":"2005","unstructured":"Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin J-P, Davenport AP, Spedding M, Harmar AJ: International Union of Pharmacology. XLVI. G Protein-Coupled Receptor List. Pharmacol Rev 2005, 57(2):279\u2013288. 10.1124\/pr.57.2.5","journal-title":"Pharmacol Rev"},{"issue":"1","key":"3773_CR25","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1093\/nar\/gkg103","volume":"31","author":"F Horn","year":"2003","unstructured":"Horn F, Bettler E, Oliveira L, Campagne F, Cohen FE, Vriend G: GPCRDB information system for G protein-coupled receptors. Nucl Acids Res 2003, 31(1):294\u2013297. 10.1093\/nar\/gkg103","journal-title":"Nucl Acids Res"},{"issue":"3","key":"3773_CR26","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/sj.bjp.0706048","volume":"144","author":"JG Baker","year":"2005","unstructured":"Baker JG: The selectivity of \u03b2-adrenoceptor antagonists at the human \u03b21, \u03b22and \u03b23adrenoceptors. Br J Pharmacol 2005, 144(3):317\u2013322. 10.1038\/sj.bjp.0706048","journal-title":"Br J Pharmacol"},{"issue":"1","key":"3773_CR27","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/BF00877757","volume":"9","author":"PA Van Zwieten","year":"1995","unstructured":"Van Zwieten PA, Doods HN: Muscarinic receptors and drugs in cardiovascular medicine. Cardiovascular Drugs and Therapy 1995, 9(1):159\u2013167. 10.1007\/BF00877757","journal-title":"Cardiovascular Drugs and Therapy"},{"issue":"1","key":"3773_CR28","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1124\/mol.64.1.21","volume":"64","author":"U Voigtl\u00e4nder","year":"2003","unstructured":"Voigtl\u00e4nder U, J\u00f6hren K, Mohr M, Raasch A, Tr\u00e4nkle C, Buller S, Ellis J, H\u00f6ltje H-D, Mohr K: Allosteric site on muscarinic acetylcholine receptors: identification of two amino acids in the muscarinic M2 receptor that account entirely for the M2\/M5 subtype selectivities of some structurally diverse allosteric ligands in N-methylscopolamine-occupied receptors. Molecular Pharmacology 2003, 64(1):21\u201331. 10.1124\/mol.64.1.21","journal-title":"Molecular Pharmacology"},{"issue":"suppl_1","key":"3773_CR29","first-page":"D907","volume":"36","author":"Y Okuno","year":"2008","unstructured":"Okuno Y, Tamon A, Yabuuchi H, Niijima S, Minowa Y, Tonomura K, Kunimoto R, Feng C: GLIDA: GPCR ligand database for chemical genomics drug discovery database and tools update. Nucl Acids Res 2008, 36(suppl_1):D907\u2013912.","journal-title":"Nucl Acids Res"},{"issue":"7","key":"3773_CR30","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1038\/nbt1228","volume":"24","author":"GV Paolini","year":"2006","unstructured":"Paolini GV, Shapland RHB, van Hoorn WP, Mason JS, Hopkins AL: Global mapping of pharmacological space. Nat Biotech 2006, 24(7):805\u2013815. 10.1038\/nbt1228","journal-title":"Nat Biotech"},{"issue":"4","key":"3773_CR31","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1021\/jm061180b","volume":"50","author":"S Cuisiat","year":"2007","unstructured":"Cuisiat S, Bourdiol N, Lacharme V, Newman-Tancredi A, Colpaert F, Vacher B: Towards a New Generation of Potential Antipsychotic Agents Combining D2 and 5-HT1A Receptor Activities. J Med Chem 2007, 50(4):865\u2013876. 10.1021\/jm061180b","journal-title":"J Med Chem"},{"issue":"2","key":"3773_CR32","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/sj.bjp.0707164","volume":"151","author":"AJ Lawrence","year":"2007","unstructured":"Lawrence AJ: Optimisation of anti-psychotic therapeutics: a balancing act? Br J Pharmacol 2007, 151(2):161\u2013162. 10.1038\/sj.bjp.0707164","journal-title":"Br J Pharmacol"},{"issue":"4","key":"3773_CR33","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1021\/jm0309452","volume":"47","author":"K Bondensgaard","year":"2004","unstructured":"Bondensgaard K, Ankersen M, Thogersen H, Hansen BS, Wulff BS, Bywater RP: Recognition of Privileged Structures by G-Protein Coupled Receptors. J Med Chem 2004, 47(4):888\u2013899. 10.1021\/jm0309452","journal-title":"J Med Chem"},{"issue":"6","key":"3773_CR34","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1021\/jm0502900","volume":"49","author":"DM Schnur","year":"2006","unstructured":"Schnur DM, Hermsmeier MA, Tebben AJ: Are Target-Family-Privileged Substructures Truly Privileged? J Med Chem 2006, 49(6):2000\u20132009. 10.1021\/jm0502900","journal-title":"J Med Chem"},{"issue":"2","key":"3773_CR35","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/S1388-1981(99)00164-X","volume":"1483","author":"M Abramovitz","year":"2000","unstructured":"Abramovitz M, Adam M, Boie Y, Carri\u00e8re M-C, Denis D, Godbout C, Lamontagne S, Rochette C, Sawyer N, Tremblay NM, et al.: The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim Biophys Acta, Mol Cell Biol Lipids 2000, 1483(2):285\u2013293. 10.1016\/S1388-1981(99)00164-X","journal-title":"Biochim Biophys Acta, Mol Cell Biol Lipids"},{"issue":"4","key":"3773_CR36","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/nrd2266","volume":"6","author":"R Pettipher","year":"2007","unstructured":"Pettipher R, Hansel TT, Armer R: Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov 2007, 6(4):313\u2013325. 10.1038\/nrd2266","journal-title":"Nat Rev Drug Discov"},{"issue":"52","key":"3773_CR37","doi-asserted-by":"publisher","first-page":"40686","DOI":"10.1074\/jbc.M004512200","volume":"275","author":"S Wang","year":"2000","unstructured":"Wang S, Gustafson E, Pang L, Qiao X, Behan J, Maguire M, Bayne M, Laz T: A Novel Hepatointestinal Leukotriene B4 Receptor. Cloning and Functional Characterization. J Biol Chem 2000, 275(52):40686\u201340694. 10.1074\/jbc.M004512200","journal-title":"J Biol Chem"},{"issue":"6633","key":"3773_CR38","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1038\/42506","volume":"387","author":"T Yokomizo","year":"1997","unstructured":"Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T: A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997, 387(6633):620\u2013624. 10.1038\/42506","journal-title":"Nature"},{"issue":"1","key":"3773_CR39","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1023\/A:1022686622752","volume":"3","author":"S Le Crom","year":"2003","unstructured":"Le Crom S, Kapsimali M, Bar\u00f4me P-O, Vernier P: Dopamine receptors for every species: Gene duplications and functional diversification in Craniates. Journal of Structural and Functional Genomics 2003, 3(1):161\u2013176. 10.1023\/A:1022686622752","journal-title":"Journal of Structural and Functional Genomics"},{"issue":"2","key":"3773_CR40","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1002\/med.20130","volume":"29","author":"J Zhang","year":"2009","unstructured":"Zhang J, Xiong B, Zhen X, Zhang A: Dopamine D1 receptor ligands: where are we now and where are we going. Med Res Rev 2009, 29(2):272\u2013294. 10.1002\/med.20130","journal-title":"Med Res Rev"},{"issue":"1-2","key":"3773_CR41","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/S1566-2772(03)00021-5","volume":"3","author":"BL Roth","year":"2003","unstructured":"Roth BL, Sheffler D, Potkin SG: Atypical antipsychotic drug actions: unitary or multiple mechanisms for 'atypicality'? Clinical Neuroscience Research 2003, 3(1\u20132):108\u2013117. 10.1016\/S1566-2772(03)00021-5","journal-title":"Clinical Neuroscience Research"},{"key":"3773_CR42","doi-asserted-by":"crossref","unstructured":"Coward DM: General pharmacology of clozapine. The British Journal of Psychiatry Supplement 1992, (17):5\u201311.","DOI":"10.1192\/S0007125000296840"},{"issue":"5-6","key":"3773_CR43","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1159\/000063562","volume":"59","author":"HH Zakon","year":"2002","unstructured":"Zakon HH: Convergent Evolution on the Molecular Level. Brain, Behavior and Evolution 2002, 59(5\u20136):250\u2013261. 10.1159\/000063562","journal-title":"Brain, Behavior and Evolution"},{"issue":"9","key":"3773_CR44","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nbt0908-983","volume":"26","author":"J Mestres","year":"2008","unstructured":"Mestres J, Gregori-Puigjane E, Valverde S, Sole RV: Data completeness--the Achilles heel of drug-target networks. Nat Biotech 2008, 26(9):983\u2013984. 10.1038\/nbt0908-983","journal-title":"Nat Biotech"},{"issue":"15","key":"3773_CR45","doi-asserted-by":"publisher","first-page":"2887","DOI":"10.1021\/jm9602928","volume":"39","author":"GW Bemis","year":"1996","unstructured":"Bemis GW, Murcko MA: The Properties of Known Drugs. 1. Molecular Frameworks. J Med Chem 1996, 39(15):2887\u20132893. 10.1021\/jm9602928","journal-title":"J Med Chem"},{"key":"3773_CR46","volume-title":"Fragment-Based Drug Discovery: A Practical Approach","author":"E van der Horst","year":"2008","unstructured":"van der Horst E, IJzerman AP: Computational Approaches to Fragment and Substructure Discovery and Evaluation. In Fragment-Based Drug Discovery: A Practical Approach. Edited by: Zartler ER, Shapiro J, Chichester M. West Sussex, U.K.: John Wiley & Sons, Ltd; 2008."},{"issue":"7","key":"3773_CR47","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1177\/1087057107306759","volume":"12","author":"P Bernasconi","year":"2007","unstructured":"Bernasconi P, Min C, Galasinski S, Popa-Burke I, Bobasheva A, Coudurier L, Birkos S, Hallam R, Janzen WP: A Chemogenomic Analysis of the Human Proteome: Application to Enzyme Families. J Biomol Screen 2007, 12(7):972\u2013982. 10.1177\/1087057107306759","journal-title":"J Biomol Screen"},{"key":"3773_CR48","unstructured":"ChEMBL[http:\/\/www.ebi.ac.uk\/chembl\/]"},{"issue":"2","key":"3773_CR49","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.pharmthera.2004.03.004","volume":"102","author":"BL Roth","year":"2004","unstructured":"Roth BL, Lopez E, Beischel S, Westkaemper RB, Evans JM: Screening the receptorome to discover the molecular targets for plant-derived psychoactive compounds: a novel approach for CNS drug discovery. Pharmacol Ther 2004, 102(2):99\u2013110. 10.1016\/j.pharmthera.2004.03.004","journal-title":"Pharmacol Ther"},{"issue":"suppl_1","key":"3773_CR50","first-page":"D190","volume":"36","author":"The UniProt Consortium","year":"2008","unstructured":"The UniProt Consortium: The Universal Protein Resource (UniProt). Nucl Acids Res 2008, 36(suppl_1):D190\u2013195.","journal-title":"Nucl Acids Res"},{"key":"3773_CR51","doi-asserted-by":"crossref","unstructured":"Wheeler DL, Barrett T, Benson DA, Bryant SH, Canese K, Chetvernin V, Church DM, DiCuccio M, Edgar R, Federhen S, et al.: Database resources of the National Center for Biotechnology Information. Nucl Acids Res 2008, (36 Database):D13-D21.","DOI":"10.1093\/nar\/gkm1000"},{"issue":"suppl_1","key":"3773_CR52","doi-asserted-by":"publisher","first-page":"D668","DOI":"10.1093\/nar\/gkj067","volume":"34","author":"DS Wishart","year":"2006","unstructured":"Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J: DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucl Acids Res 2006, 34(suppl_1):D668\u2013672. 10.1093\/nar\/gkj067","journal-title":"Nucl Acids Res"},{"key":"3773_CR53","unstructured":"GPCRDB[http:\/\/www.gpcr.org\/7tm\/]"},{"key":"3773_CR54","unstructured":"GASTON[http:\/\/www.liacs.nl\/~snijssen\/gaston\/]"},{"key":"3773_CR55","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1007\/11564126_39","volume-title":"Knowledge Discovery in Databases: PKDD 2005","author":"M W\u00f6rlein","year":"2005","unstructured":"W\u00f6rlein M, Meinl T, Fischer I, Philippsen M: A Quantitative Comparison of the Subgraph Miners MoFa, gSpan, FFSM, and Gaston. Knowledge Discovery in Databases: PKDD 2005 2005, 392\u2013403. full_text"},{"key":"3773_CR56","first-page":"487","volume-title":"Proceedings of the 20th International Conference on Very Large Data Bases: September 12 - 15 1994","author":"R Agrawal","year":"1994","unstructured":"Agrawal R, Srikant R: Fast Algorithms for Mining Association Rules in Large Databases. In Proceedings of the 20th International Conference on Very Large Data Bases: September 12 - 15 1994. Morgan Kaufmann Publishers, San Francisco, CA; 1994:487\u2013499."},{"key":"3773_CR57","volume-title":"PHYLIP (Phylogeny Inference Package) version 3.6. Distributed by the author. Department of Genome Sciences, University of Washington, Seattle","author":"J Felsenstein","year":"2005","unstructured":"Felsenstein J: PHYLIP (Phylogeny Inference Package) version 3.6. Distributed by the author. Department of Genome Sciences, University of Washington, Seattle. 2005."},{"issue":"8","key":"3773_CR58","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1093\/molbev\/msm092","volume":"24","author":"K Tamura","year":"2007","unstructured":"Tamura K, Dudley J, Nei M, Kumar S: MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) Software Version 4.0. Mol Biol Evol 2007, 24(8):1596\u20131599. 10.1093\/molbev\/msm092","journal-title":"Mol Biol Evol"},{"issue":"4","key":"3773_CR59","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1177\/108705719600100404","volume":"1","author":"CD Garr","year":"1996","unstructured":"Garr CD, Peterson JR, Schultz L, Oliver AR, Underiner TL, Cramer RD, Ferguson AM, Lawless MS, Patterson DE: Solution Phase Synthesis of Chemical Libraries for Lead Discovery. J Biomol Screen 1996, 1(4):179\u2013186. 10.1177\/108705719600100404","journal-title":"J Biomol Screen"}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-11-316.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T05:27:08Z","timestamp":1630474028000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-11-316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,6,10]]},"references-count":59,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2010,12]]}},"alternative-id":["3773"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-11-316","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,6,10]]},"assertion":[{"value":"4 March 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2010","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2010","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"316"}}