Modeling the Similarity and Divergence of Dopamine D<sub>2</sub>-like Receptors and Identification of Validated Ligand−Receptor Complexes

Boeckler, Frank M.; Lanig, Harald; Gmeiner, Peter

doi:10.1021/jm049612a

Cited by 43 publications

(72 citation statements)

References 71 publications

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“…We found the pyridine moiety of MLS1547 preferred to point toward TM2. Interestingly, for two well studied D2R antagonists, spiperone and azaperone, that share a common 4-fluophenyl-4-butanone moiety, as proposed/validated previously (Boeckler et al, 2005), if we assume that such a moiety is bound in the OBS, then the pyridine moiety of azaperone points toward TM2, similar to MLS1547 (data not shown). We also docked MLS1547 in another D2R model in an active conformation based on a D3R active model (Newman et al, 2012) and equilibrated using molecular dynamics simulations.…”

Section: Methodssupporting

confidence: 60%

Discovery and Characterization of a G Protein–Biased Agonist That Inhibits β-Arrestin Recruitment to the D2 Dopamine Receptor

Free¹,

Chun²,

Moritz³

et al. 2014

Mol Pharmacol

118

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A high-throughput screening campaign was conducted to interrogate a 380,0001 small-molecule library for novel D2 dopamine receptor modulators using a calcium mobilization assay. Active agonist compounds from the primary screen were examined for orthogonal D2 dopamine receptor signaling activities including cAMP modulation and b-arrestin recruitment. Although the majority of the subsequently confirmed hits activated all signaling pathways tested, several compounds showed a diminished ability to stimulate b-arrestin recruitment. One such compound (MLS1547; 5-chloro-7-[(4-pyridin-2-ylpiperazin-1-yl)methyl]quinolin-8-ol) is a highly efficacious agonist at D2 receptor-mediated G protein-linked signaling, but does not recruit b-arrestin as demonstrated using two different assays. This compound does, however, antagonize dopaminestimulated b-arrestin recruitment to the D2 receptor. In an effort to investigate the chemical scaffold of MLS1547 further, we characterized a set of 24 analogs of MLS1547 with respect to their ability to inhibit cAMP accumulation or stimulate b-arrestin recruitment. A number of the analogs were similar to MLS1547 in that they displayed agonist activity for inhibiting cAMP accumulation, but did not stimulate b-arrestin recruitment (i.e., they were highly biased). In contrast, other analogs displayed various degrees of G protein signaling bias. These results provided the basis to use pharmacophore modeling and molecular docking analyses to build a preliminary structure-activity relationship of the functionally selective properties of this series of compounds. In summary, we have identified and characterized a novel G protein-biased agonist of the D2 dopamine receptor and identified structural features that may contribute to its biased signaling properties.

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Section: Methodssupporting

confidence: 60%

Discovery and Characterization of a G Protein–Biased Agonist That Inhibits β-Arrestin Recruitment to the D2 Dopamine Receptor

Free¹,

Chun²,

Moritz³

et al. 2014

Mol Pharmacol

118

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“…In an explicit homology model, individual rotamer positions are assigned to all amino acids, and the model is then typically refined by molecular dynamics or stepwise relaxation steps folding the side chains around a number of known ligands. While there are various techniques described in the literature to arrive at state-of-the-art homology models, 23,24 they all stress the need of additional information from highly potent ligands 7,[23][24][25][26][27][28][29][30][31][32]34,35 and of several refinement cycles. There is no reference point by which the accuracy of such models can be judged, except for consistency with known rules about protein folding.…”

Section: Discussionmentioning

confidence: 99%

“…This procedure replaces any interactive knowledge-based refinement of the alignment required after using standard bioinformatics alignment tools. 26 The opsin family is used as a reference because of the available X-ray crystal structure of bovine rhodopsin. 18 In a second step, amino acids of the aligned sequence positions involved in ligand binding are extracted.…”

Section: Methodsmentioning

confidence: 99%

“…23,24 To obtain high-quality homology models suitable for docking experiments, additional, work-intensive refinement cycles are needed that explicitly take into account binding studies with highly potent ligands. 7,21,23,[25][26][27][28][29][30][31][32][33][34][35] This kind of approach is very valuable for optimizations of medicinal chemistry series in advanced projects on wellcharacterized targets, where mutational data and structureactivity relationships for the ligands are available and can be incorporated into validation cycles of the models. In earlystage GPCR projects, however, where often only the natural ligands are known and data from site-directed mutagenesis are missing, a traditional GPCR homology model with its focus on atomic details may turn out to be of only limited use.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Kratochwil

Malherbe

Lindemann

et al. 2005

J. Chem. Inf. Model.

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G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Here, a comprehensive and automated method allowing fast analysis and comparison of these putative binding pockets across the entire GPCR family is presented. The method relies on a robust alignment algorithm based on conservation indices, focusing on pharmacophore-like relationships between amino acids. Analysis of conservation patterns across the GPCR family and alignment to the rhodopsin X-ray structure allows the extraction of the amino acids lining the TM binding pocket in a so-called ligand binding pocket vector (LPV). In a second step, LPVs are translated to simple 3D receptor pharmacophore models, where each amino acid is represented by a single spherical pharmacophore feature and all atomic detail is omitted. Applications of the method include the assessment of selectivity issues, support of mutagenesis studies, and the derivation of rules for focused screening to identify chemical starting points in early drug discovery projects. Because of the coarseness of this 3D receptor pharmacophore model, however, meaningful scoring and ranking procedures of large sets of molecules are not justified. The LPV analysis of the trace amine-associated receptor family and its experimental validation is discussed as an example. The value of the 3D receptor model is demonstrated for a class C GPCR family, the metabotropic glutamate receptors.

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“…The CWXP motif in TM 6 is known to be conserved in family A of the GPCRs [26]. The CWXP motif is preserved in the fatty acid binding receptors except in GPR119, where the cystine is replaced by a serine.…”

Section: Homology Of Fatty Acid Binding Receptors To Class a Gpcrs Amentioning

confidence: 99%

Fatty Acid Binding Receptors and Their Physiological Role in Type 2 Diabetes

Swaminath

2008

Archiv der Pharmazie

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G‐protein‐coupled receptors (GPCRs) respond to various physiological ligands such as photons, ions, and small molecules that include amines, fatty acids, and amino acids to peptides, proteins and steroids. Therefore, this family of proteins represents an attractive target for biopharmaceutical research [1]. The physiological role of fatty acids and other lipid molecules as important signal mediators is well studied in various metabolic pathways [2]. Acute administration of free fatty acids (FFAs) stimulates insulin release. Conversely, chronic exposure to high levels of free fatty acids leads to impairment of β cell function and lipotoxicity. However, the receptors through which these fatty acids and lipids act were unknown, until the identification of fatty acid binding receptors: GPR40, GPR41, GPR43, and GPR119. Based on their tissue‐expression profile, and pharmacologic analysis, the fatty acid binding receptors along with lipid binding receptor GPR119 are linked to diabetes and obesity. They play a critical role in the metabolic regulation of insulin release and glucose homeostasis. In this review, the mechanism of receptor activation, pharmacology, and the physiological functions of the fatty acid binding receptors will be discussed.

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Modeling the Similarity and Divergence of Dopamine D₂-like Receptors and Identification of Validated Ligand−Receptor Complexes

Cited by 43 publications

References 71 publications

Discovery and Characterization of a G Protein–Biased Agonist That Inhibits β-Arrestin Recruitment to the D2 Dopamine Receptor

Discovery and Characterization of a G Protein–Biased Agonist That Inhibits β-Arrestin Recruitment to the D2 Dopamine Receptor

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Fatty Acid Binding Receptors and Their Physiological Role in Type 2 Diabetes

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Modeling the Similarity and Divergence of Dopamine D2-like Receptors and Identification of Validated Ligand−Receptor Complexes

Cited by 43 publications

References 71 publications

Discovery and Characterization of a G Protein–Biased Agonist That Inhibits β-Arrestin Recruitment to the D2 Dopamine Receptor

Discovery and Characterization of a G Protein–Biased Agonist That Inhibits β-Arrestin Recruitment to the D2 Dopamine Receptor

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Fatty Acid Binding Receptors and Their Physiological Role in Type 2 Diabetes

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Product

Resources

About

Modeling the Similarity and Divergence of Dopamine D₂-like Receptors and Identification of Validated Ligand−Receptor Complexes