Hybrid approach for the design of highly affine and selective dopamine D3 receptor ligands using privileged scaffolds of biogenic amine GPCR ligands

Sasse, Britta C.; Mach, Ulrich R.; Leppaenen, Jukka; Calmels, Thierry; Stark, Holger

doi:10.1016/j.bmc.2007.08.034

Cited by 24 publications

(17 citation statements)

References 47 publications

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“…Imbalance of the dopaminergic system is implicated in several neurological and neuropsychiatric disorders, such as Parkinson's disease, Huntington's disease, schizophrenia, Tourette's syndrome, and drug abuse [1,[3][4][5][6][7]. All dopamine receptor subtypes belong to class A of G-protein coupled receptors [8][9][10] (GPCRs) super family, and are divided into two families [11,12] due to the basic pharmacological profiles: D 1 -like receptors including the dopamine D 1 and the D 5 receptors, are characterized by activation of adenyl acetyl cyclase mediated by stimulatory G s protein, while D 2 -like receptors consist of the dopamine D 2 , D 3 and D 4 receptors, which couple to inhibitory G i/o proteins and inhibit adenyl cyclase [13,14].…”

Section: Introductionmentioning

confidence: 99%

Selectivity and activation of dopamine D3R from molecular dynamics

Feng

Hou

2012

J Mol Model

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D(3) receptor, a member of dopamine (DA) D(2)-like receptor family, which belongs to class A of G-protein coupled receptors (GPCRs), has been reported to play a critical role in neuropsychiatric disorders. Recently, the crystal structure of human dopamine D3 receptor was reported, which facilitates structure-based drug discovery of D3R significantly. We dock D3R-selective compounds into the crystal structure of D3R and homology structure of D2R. Then we perform 20 ns molecular dynamics (MD) of the receptor with selective compounds bound in explicit lipid and water. Our docking and MD results indicate the important residues related to the selectivity of D3R. Specifically, residue Thr(7.39) in D3R may contribute to the high selectivity of R-22 with D3R. Meanwhile, the 4-carbon linker and phenylpiperazine of R-22 improve the binding affinity and the selectivity with D3R. We also dock the agonists, including dopamine, into D3R and perform MD. Our molecular dynamics results of D3R with agonist bound show strong conformational changes from TM5, TM6, and TM7, outward movement of intracellular part of TM6, fluctuation of "ionic lock" motif and conformational change of Tyr(7.53), which is consistent with recent crystal structures of active GPCRs and illustrates the dynamical process during activation. Our results reveal the mechanism of selectivity and activation for D3R, which is important for developing high selective antagonists and agonists for D3R.

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Section: Introductionmentioning

confidence: 99%

Selectivity and activation of dopamine D3R from molecular dynamics

Feng

Hou

2012

J Mol Model

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“…Asp110 3.32 is highly conserved in all aminergic receptors. Three active molecules (activity smaller than 10 μ M) of the D3 receptor (ChEMBL [15,16] target ID 130) from three different scientific papers [17-19] were extracted from the ChEMBL database (Figure 1). Molecule 1 was selected as reference compound and the other two as test molecules.…”

Section: Resultsmentioning

confidence: 99%

Similarity maps - a visualization strategy for molecular fingerprints and machine-learning methods

2013

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Fingerprint similarity is a common method for comparing chemical structures. Similarity is an appealing approach because, with many fingerprint types, it provides intuitive results: a chemist looking at two molecules can understand why they have been determined to be similar. This transparency is partially lost with the fuzzier similarity methods that are often used for scaffold hopping and tends to vanish completely when molecular fingerprints are used as inputs to machine-learning (ML) models. Here we present similarity maps, a straightforward and general strategy to visualize the atomic contributions to the similarity between two molecules or the predicted probability of a ML model. We show the application of similarity maps to a set of dopamine D3 receptor ligands using atom-pair and circular fingerprints as well as two popular ML methods: random forests and naïve Bayes. An open-source implementation of the method is provided.

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“…Utilizing previously published synthetic routes, norketotifen (Sasse et al 2007) (WR621341), the N-oxide (WR621362) and 10-hydroxy (WR621365) products (Waldvogel et al 1976) were synthesized in high yield from commercially available ketotifen fumarate (purchased from AK Scientific, Union City, CA).…”

Section: Compoundsmentioning

confidence: 99%

Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy

Milner

Sousa

Pybus

et al. 2012

Eur J Drug Metab Pharmacokinet

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Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.

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Hybrid approach for the design of highly affine and selective dopamine D3 receptor ligands using privileged scaffolds of biogenic amine GPCR ligands

Cited by 24 publications

References 47 publications

Selectivity and activation of dopamine D3R from molecular dynamics

Selectivity and activation of dopamine D3R from molecular dynamics

Similarity maps - a visualization strategy for molecular fingerprints and machine-learning methods

Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy

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