The clear distinction between the two dopamine receptor types, i.e. D1 and D5 (D1-like) versus D2, D3, and D4 (D2-like), exists both in the sequence-based classification and ligand-based classification. The British Journal of Psychiatry Supplement 1992, (17):5–11.Zakon HH: Convergent Evolution on the Molecular Level. Chem Med Chem 2006, 1(8):760–782.View ArticleGoogle ScholarJaakola 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. Interestingly, the adenosine A1 and A3 receptors, which are also purinergic, identify most (28 out of 42) of the P2Y1 ligands.
Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure. This allowed us to merge the set with the rest of the data. KiDB provides information on drugs and molecular compounds that interact with GPCRs, ion channels, transporters, and enzymes. This is based on the fact that most prostanoid receptor ligands are direct derivatives of the endogenous ligands [35, 36], the so-called eicosanoids. Curr Opin Drug Discovery Dev 2001, 4(5):561–574.Google ScholarCherezov 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 β2-Adrenergic G Protein Coupled Receptor.
The interpretation of this plot is as follows. This may imply that ligands for these receptor subtypes are non-selective, such as the adenosine receptor antagonists caffeine and theophylline. Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D2 receptor agonists. J. Med. Two distance matrices represented the similarities of the receptors: according to the frequent substructures of their ligands and the 7-TM domain sequence alignment, both were visualized as a phylogenetic tree, with receptors as leaves of the tree.
From these, a consensus tree was built. MEGA4  was used for editing the layout of the trees and for visualization. Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists. J. Med. Chem. Lett. 17, 3754–3759 (2007). Irwin, J.J., Sterling, T., Mysinger, M.M., Bolstad, E.S. & Coleman, R.G. ZINC: a free tool to discover chemistry for biology. J. Chem. Acad. Sci. USA 109, 11178–11183 (2012). Kumar, S., Tamura, K. & Nei, M. MEGA3: Integrated software for molecular evolutionary genetics analysis and sequence alignment.
The delta-delta plot reveals how receptor locations behave globally with respect to the median of all receptors. It was used to visualize the differences in location of each receptor in sequence space and in substructure space. Scarcity of ligand data is reflected in the substructure profiles, thereby influencing the correlations among receptors.
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Ligands are annotated with an activity type, namely: full agonist, partial agonist, agonist, antagonist or inverse agonist. In the present study, we focused only on binding affinity and not on the activity type. Cloning and Functional Characterization. J Biol Chem 2000, 275(52):40686–40694. 10.1074/jbc.M004512200View ArticlePubMedGoogle ScholarYokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T: A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. The square root of the sum of all squared differences is the Euclidean distance between a molecule and a class.
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The difference between ligand-based and target-based classifications may be due to convergent evolution . Functional convergence denotes how proteins that differ in sequence may fulfill the same protein function. For instance, with the exclusion of the glycoprotein, P2Y, angiotensin, and bradykinin receptors, all other receptors represented by two subtypes occur in pairs in both the ligand tree and the sequence tree. Curr Opin Struct Biol 2013, 23: 185–190. 10.1016/j.sbi.2013.01.008View ArticlePubMedGoogle ScholarCostanzi S, Wang K: The GPCR crystallography boom: providing an invaluable source of structural information and expanding the scope of homology modeling.
Science 2008, 1164772.Google ScholarBallesteros J, Palczewski K: G protein-coupled receptor drug discovery: Implications from the crystal structure of rhodopsin. Targets were analyzed based on the substructure profiles of their ligands using an unbiased approach. Targets that are, on average, more distant from the rest are plotted further away from the origin; targets plotted above the diagonal are more distant in sequence space, while targets plotted below the diagonal are more distant in substructure space.
This plot is an adaptation from the delta-delta plot in Garr et al.. It is a new way of tree comparison, which visualizes the differences among trees graphically, as opposed to the sole calculation of a numerical distance between two trees which is not trivial to interpret. Science 2007, 318(5854):1258–1265. 10.1126/science.1150577View ArticlePubMedPubMed CentralGoogle ScholarWarne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AGW, Tate CG, Schertler GFX: Structure of a β1-adrenergic G-protein-coupled receptor. However, in sequence space these receptors are at great distance (at positions 91 and 92, respectively).Figure 4 Examples of plotted scores for the leave-one-out validation.
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