Definition of a Pharmacophore for Partial Agonists of Serotonin 5-HT<sub>3</sub> Receptors

Daveu, Cyril; Bureau, Ronan; Baglin, Isabelle; Prunier, H.; Lancelot, Jean‐Charles; Rault, Syl­vain

doi:10.1021/ci980153u

Cited by 33 publications

(19 citation statements)

References 35 publications

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“…Models 1, 2, 3, 6, and 7 all display one potential hydrogenbonding interaction with 5-HT, whereas models 4 and 5 have three positions for potential hydrogen bonds: with the backbone of S182 and the functional groups of E236 and N128. Not only would this favor tight binding of 5-HT in these two models, but also it is supported by an experimentally derived model of the pharmacophore for partial agonists (Daveu et al, 1999). This pharmacophore identifies two important hydrogen-bonding interactions at opposite ends of the ligand, which resemble those shown by models 4 and 5 described above.…”

Section: Discussionmentioning

confidence: 63%

Prediction of 5-HT3 Receptor Agonist-Binding Residues Using Homology Modeling

Reeves¹,

Sayed

Chau³

et al. 2003

Biophysical Journal

108

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5-HT(3) receptors demonstrate significant structural and functional homology to other members of the Cys-loop ligand-gated ion channel superfamily. The extracellular domains of these receptors share similar sequence homology (approximately 20%) with Limnaea acetylcholine binding protein, for which an x-ray crystal structure is available. We used this structure as a template for computer-based homology modeling of the 5-HT(3) receptor extracellular domain. AutoDock software was used to dock 5-HT into the putative 5-HT(3) receptor ligand-binding site, resulting in seven alternative energetically favorable models. Residues located no more than 5 A from the docked 5-HT were identified for each model; of these, 12 were found to be common to all seven models with five others present in only certain models. Some docking models reflected the cation-pi interaction previously demonstrated for W183, and data from these and other studies were used to define our preferred models.

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Section: Discussionmentioning

confidence: 63%

Prediction of 5-HT3 Receptor Agonist-Binding Residues Using Homology Modeling

Reeves¹,

Sayed

Chau³

et al. 2003

Biophysical Journal

108

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“…The chemical structures of four known Vpu blockers were retrieved from the literature [ 20 ]. The 3D conformations were generated using the (default) MMFF94x forcefield [ 30 ], using the MOE software tool [ 31 ], following the protocol previously implemented by Daveu et al [ 32 ]. The force field parameters were kept at their default values of the Strain Limit of 4 kcal/mol and the Conformations limit of 250 conformations/molecule.…”

Section: Methodsmentioning

confidence: 99%

Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

et al. 2015

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The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world.

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“…40,42,43 CATALYST 4.5 39 software supports the HypoGen algorithm, which is able to generate pharmacophoric hypotheses from a set of compounds known to be active at a specific target, by means of identification of common features present in the active but absent in the inactive molecules of the training set. Previously reported models developed by HypoGen have been successfully used to suggest new directions in lead discovery [44][45][46][47][48][49] and for searching databases to identify new structural classes of potential lead candidates. 50 The following values were chosen: spacing (1.00-2.95 Å), weight variation (1.0), tolerance variation (1.0), mapping coefficient (0), and activity uncertainty (3).…”

Section: Methodsmentioning

confidence: 99%

Optimization of the Pharmacophore Model for 5-HT₇R Antagonism. Design and Synthesis of New Naphtholactam and Naphthosultam Derivatives

et al. 2003

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We present in this study an optimization of a preliminary pharmacophore model for 5-HT(7)R antagonism, with the incorporation of recently reported ligands and using an efficient procedure with the CATALYST program. The model consists of five features: a positive ionizable atom (PI), a H-bonding acceptor group (HBA), and three hydrophobic regions (HYD). This model has been supported by the design, synthesis, and biological evaluation of new naphtholactam and naphthosultam derivatives of general structure I (39-72). A systematic structure-affinity relationship (SAFIR) study on these analogues has allowed us to confirm that the model incorporates the essential structural features for 5-HT(7)R antagonism. In addition, computational simulation of the complex between compound 56 and a rhodopsin-based 3D model of the 5-HT(7)R transmembrane domain has permitted us to define the molecular details of the ligand-receptor interaction and gives additional support to the proposed pharmacophore model for 5-HT(7)R antagonism: (i) the HBA feature of the pharmacophore model binds Ser(5.42) and Thr(5.43), (ii) the HYD1 feature interacts with Phe(6.52), (iii) the PI feature forms an ionic interaction with Asp(3.32), and (iv) the HYD3 (AR) feature interacts with a set of aromatic residues (Phe(3.28), Tyr(7.43)). These results provide the tools for the design and synthesis of new ligands with predetermined affinities and pharmacological properties.

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Definition of a Pharmacophore for Partial Agonists of Serotonin 5-HT₃ Receptors

Cited by 33 publications

References 35 publications

Prediction of 5-HT3 Receptor Agonist-Binding Residues Using Homology Modeling

Prediction of 5-HT3 Receptor Agonist-Binding Residues Using Homology Modeling

Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

Optimization of the Pharmacophore Model for 5-HT₇R Antagonism. Design and Synthesis of New Naphtholactam and Naphthosultam Derivatives

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Definition of a Pharmacophore for Partial Agonists of Serotonin 5-HT3 Receptors

Cited by 33 publications

References 35 publications

Prediction of 5-HT3 Receptor Agonist-Binding Residues Using Homology Modeling

Prediction of 5-HT3 Receptor Agonist-Binding Residues Using Homology Modeling

Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

Optimization of the Pharmacophore Model for 5-HT7R Antagonism. Design and Synthesis of New Naphtholactam and Naphthosultam Derivatives

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Product

Resources

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Definition of a Pharmacophore for Partial Agonists of Serotonin 5-HT₃ Receptors

Optimization of the Pharmacophore Model for 5-HT₇R Antagonism. Design and Synthesis of New Naphtholactam and Naphthosultam Derivatives