Identification of the binding sites and selectivity of sarpogrelate, a novel 5-HT2 antagonist, to human 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes by molecular modeling

Rashid, Mamunur; Manivet, Philippe; Nishio, Hiroaki; Pratuangdejkul, Jaturong; Rajab, Mohamed S.; Ishiguro, Masaji; Launay, Jean Marie; Nagatomo, Takafumi

doi:10.1016/s0024-3205(03)00227-3

Cited by 61 publications

(49 citation statements)

References 31 publications

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“…37 Choudhary et al mentioned that Phe339 and Phe340 (Phe327 and Phe328 in 5-HT 2C receptor) having effect on binding of 5-HT, DOI and few other ligands. 38 Homology modeling study with rhodopsin has shown Trp324, Phe327 and Phe328 residues make hydrophobic box near the ligand 39 which is in good agreement with our model. For further validation of the model, binding mode of partial inverse agonist carazolol in β2AR crystal structure is compared with one of the docked ligand (Compound 2) in 5-HT 2C receptor.…”

supporting

confidence: 82%

Binding Mode Prediction of 5-Hydroxytryptamine 2C Receptor Ligands by Homology Modeling and Molecular Docking Analysis

Ahmed¹,

Nagarajan²,

Doddareddy³

et al. 2011

Bulletin of the Korean Chemical Society

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Serotonin or 5-hydroxytryptamine subtype 2C (5-HT 2C ) receptor belongs to class A amine subfamily of Gprotein-coupled receptor (GPCR) super family and its ligands has therapeutic promise as anti-depressant and -obesity agents. So far, bovine rhodopsin from class A opsin subfamily was the mostly used X-ray crystal template to model this receptor. Here, we explained homology model using beta 2 adrenergic receptor (β2AR), the model was energetically minimized and validated by flexible ligand docking with known agonists and antagonists. In the active site Asp134, Ser138 of transmembrane 3 (TM3), Arg195 of extracellular loop 2 (ECL2) and Tyr358 of TM7 were found as important residues to interact with agonists. In addition to these, V208 of ECL2 and N351 of TM7 was found to interact with antagonists. Several conserved residues including Trp324, Phe327 and Phe328 were also found to contribute hydrophobic interaction. The predicted ligand binding mode is in good agreement with published mutagenesis and homology model data. This new template derived homology model can be useful for further virtual screening based lead identification.

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supporting

confidence: 82%

Binding Mode Prediction of 5-Hydroxytryptamine 2C Receptor Ligands by Homology Modeling and Molecular Docking Analysis

Ahmed¹,

Nagarajan²,

Doddareddy³

et al. 2011

Bulletin of the Korean Chemical Society

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“…Molecular modeling of sarpogrelate to 5-HT 2C receptor 13) predicted that Asp3.32 in the helix 3 and Ser7.46 in the helix 7 may be the important binding sites of sarpogrelate as the hydrogen atom of the trimethyl ammonium of sarpogrelate interacts with the acidic function oxygen of Asp3.32 and carboxylate group oxygen of sarpogrelate is H-bonded by Ser7.46 OH group (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

“…Our data are consistent with the previous reports. 13,23) In case of both the Asp3.32Ala mutant and the double mutant (Asp3.32Ala-Ser7.46Ala) receptors, it was not possible to find any sarpogrelate affinity to the mutants using the radioligand as the radioligand [ 3 H]mesulergine did not show any binding to the mutants. However, sarpogrelate showed a decreased binding affinity (pKi value, 4.87Ϯ0.17) to the Ser7.46Ala mutant receptors (Fig.…”

Section: )mentioning

confidence: 99%

“…Based on radio-ligand binding and molecular modeling studies, sarpogrelate showed a moderate selectivity for 5-HT 2A receptor vs. 5-HT 2C receptor. 13) To confirm the molecular modeling data of sarpogrelate to 5-HT 2C receptors, which predicted that sarpogrelate makes strong electrostatic interactions towards Asp3.32 in transmembrane helix 3 and Ser7.46 in transmembrane helix 7 of 5-HT 2C receptors, we constructed and characterized the mutations of these amino acid residues by site-directed mutagenesis. Our findings are consistent with the molecular modeling data and suggest that these amino acid residues are important for sarpogrelate binding which have been evident from the markedly decrease in affinity of sarpogrelate for the mutant receptors.…”

mentioning

confidence: 93%

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Site-Directed Mutagenesis of the Serotonin 5-Hydroxytryptamine2C Receptor: Identification of Amino Acids Responsible for Sarpogrelate Binding

Muntasir

Takahashi

Rashid

et al. 2006

Biological & Pharmaceutical Bulletin

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“…[18][19][20][21] A recent study 22 of a novel selective 5-HT 2A receptor antagonist (AT-1015) did not show any evidence of efficacy in the treatment of intermittent claudication. In the present study on sarpogrelate (MCI-9042), which exhibits a selective antagonistic effect on 5-HT 2A receptors, and has a chemical structure different from ketanserin and AT-1015, 5,6 there was a marked training/placebo effect on ACD which persisted up to 16 weeks, despite the 6-week placebo run-in period. The extent and variability in the placebo response has always been a major difficulty in evaluating drugs in intermittent claudication.…”

Section: Discussionmentioning

confidence: 72%

Sarpogrelate, a 5-HT2A receptor antagonist in intermittent claudication. A Phase II European study

Norgren

Jawień

Mátyás³

et al. 2006

Vasc Med

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This was a multinational, multicentre, double-blind Phase II study in Europe to evaluate the efficacy and safety of two dose regimens (200 mg bid and 200 mg tid) of sarpogrelate (MCI-9042, 5-HT2A receptor antagonist) compared to placebo in patients with stable, moderately severe intermittent claudication. Following a single-blind placebo run-in period of 6 weeks, 364 (309 male and 55 female) patients (59.2 ± 8.4 years, mean SD) were randomized to receive sarpogrelate 200 mg bid, 200 mg tid or placebo for 24 weeks with a follow-up of 8 weeks. The primary objective was the increase of absolute claudication distance (ACD) at the end of treatment (week 24) compared to placebo. Analysis of covariance (ANCOVA) was performed on the log-transformed percentage of baseline ACD: loge (ACD/baseline). A responder analysis (defined as a 50% improvement in ACD) was also performed. There was a marked training/placebo effect on the ACD which persisted up to 16 weeks. At 24 weeks the primary objective did not reach statistical significance (200 mg bid vs placebo, p = 0.225; 200 mg tid vs placebo, p = 0.580). In the responder analysis, 200 mg bid showed a statistically significant difference vs placebo ( p = 0.035). In the exploratory analysis with completers (patients completing all treadmill tests), there was a statistical difference in ACD/baseline change for 200 mg bid ( p = 0.035) and in the responder analysis for 200 mg tid ( p = 0.044) at 24 weeks compared to placebo. Both treatments showed a carry-over effect for ACD during the 8-week follow-up (weeks 28-32). The treatment was well tolerated and no clinically significant safety concerns were reported. In conclusion, the study results confirm that sarpogrelate is well tolerated and although the primary endpoint failed to reach statistical significance, the responder analysis showed an increased absolute walking distance, which makes a further trial warranted, including a larger population, and possibly also a longer treatment period.

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Identification of the binding sites and selectivity of sarpogrelate, a novel 5-HT2 antagonist, to human 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes by molecular modeling

Cited by 61 publications

References 31 publications

Binding Mode Prediction of 5-Hydroxytryptamine 2C Receptor Ligands by Homology Modeling and Molecular Docking Analysis

Binding Mode Prediction of 5-Hydroxytryptamine 2C Receptor Ligands by Homology Modeling and Molecular Docking Analysis

Site-Directed Mutagenesis of the Serotonin 5-Hydroxytryptamine2C Receptor: Identification of Amino Acids Responsible for Sarpogrelate Binding

Sarpogrelate, a 5-HT2A receptor antagonist in intermittent claudication. A Phase II European study

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