Nicolas Triballeau | Centre National de la Recherche Scientifique / French National Centre for Scientific Research (original) (raw)

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Papers by Nicolas Triballeau

Research paper thumbnail of Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach

Bioorganic & Medicinal Chemistry Letters, 2010

We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold... more We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.

Research paper thumbnail of Supplemental Data High-Potency Olfactory Receptor Agonists Discovered by Virtual High-Throughput Screening: Molecular Probes for Receptor Structure and Olfactory Function

Computational protocols were designed for both ligand-based and structure-based screening workflo... more Computational protocols were designed for both ligand-based and structure-based screening workflows using the ROC curve method (Triballeau et al., 2005). Accordingly, a set of 26 active compounds identified by Speca et al. (Speca et al., 1999) (the 20 natural α-amino acids as well as agmatine, L-citrulline, L-ornithine, L-NAME, L-homoarginine and cadaverine) was divided below and above a 4 μM affinity threshold into an active and an inactive subset, respectively. This threshold corresponds to the affinity of glycine (K i = 3.9 µM) (Speca et al., 1999), which lacks a side chain capable of interacting with distal binding pocket residues (Luu et al., 2004). Thus, for any given compound, K i < 4 µM reflects stabilizing side chain interactions with the receptor, whereas K i > 4 µM reflects destabilizing side chain interactions. The ROC curve methodology allowed us to optimize parameters for both structure-based and ligand-based vHTS. Computational parameter optimization was performed iteratively by comparing the active/inactive in silico distributions with respect to the experimental data (Speca et al., 1999) and quantified by the ROC curve AUC ( ).

Research paper thumbnail of Rose Bengal analogs and vesicular glutamate transporters (VGLUTs

Bioorganic & Medicinal Chemistry, 2010

Vesicular glutamate transporters (VGLUTs) allow the loading of presynaptic glutamate vesicles and... more Vesicular glutamate transporters (VGLUTs) allow the loading of presynaptic glutamate vesicles and thus play a critical role in glutamatergic synaptic transmission. Rose Bengal (RB) is the most potent known VGLUT inhibitor (K i 25 nM); therefore we designed, synthesized and tested in brain preparations, a series of analogs based on this scaffold. We showed that among the two tautomers of RB, the carboxylic and not the lactonic form is active against VGLUTs and generated a pharmacophore model to determine the minimal structure requirements. We also tested RB specificity in other neurotransmitter uptake systems. RB proved to potently inhibit VMAT (K i 64 nM) but weakly VACHT (K i >9.7 lM) and may be a useful tool in glutamate/acetylcholine co-transmission studies.

Research paper thumbnail of Amino-Pyrrolidine Tricarboxylic Acids Give New Insight into Group III Metabotropic Glutamate Receptor Activation Mechanism

Molecular Pharmacology, 2006

Research paper thumbnail of A Virtual Screening Hit Reveals New Possibilities for Developing Group III Metabotropic Glutamate Receptor Agonists

Journal of Medicinal Chemistry, 2010

(R)-PCEP (3-amino-3-carboxypropyl-2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more (R)-PCEP (3-amino-3-carboxypropyl-2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC(50) of 1.0 +/- 0.2 microM at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC(50) of 43 +/- 16 microM and is thus significantly more potent than L-AP4 (EC(50) of 249 +/- 106 microM).

Research paper thumbnail of Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists

Proceedings of The National Academy of Sciences, 2002

Ca 2؉ , pheromones, sweet taste compounds, and the main neurotransmitters glutamate and ␥-aminobu... more Ca 2؉ , pheromones, sweet taste compounds, and the main neurotransmitters glutamate and ␥-aminobutyric acid activate G proteincoupled receptors (GPCRs) that constitute the GPCR family 3. These receptors are dimers, and each subunit has a large extracellular domain called a Venus flytrap module (VFTM), where agonists bind. This module is connected to a heptahelical domain that activates G proteins. Recently, the structure of the dimer of mGlu1 VFTMs revealed two important conformational changes resulting from glutamate binding. First, agonists can stabilize a closed state of at least one VFTM in the dimer. Second, the relative orientation of the two VFTMs in the dimer is different in the presence of glutamate, such that their C-terminal ends (which are connected to the G protein-activating heptahelical domain) become closer by more than 20 Å. This latter change in orientation has been proposed to play a key role in receptor activation. To elucidate the respective role of VFTM closure and the change in orientation of the VFTMs in family 3 GPCR activation, we analyzed the mechanism of action of the mGlu8 receptor antagonists ACPT-II and MAP4. Molecular modeling studies suggest that these two compounds prevent the closure of the mGlu8 VFTM because of ionic and steric hindrance, respectively. We show here that the replacement of the residues responsible for these hindrances (Asp-309 and Tyr-227, respectively) by Ala allows ACPT-II or MAP4 to fully activate the receptors. These data are consistent with the requirement of the VFTM closure for family 3 GPCR activation. ‡ To whom reprint requests should be addressed.

Research paper thumbnail of Virtual Screening Workflow Development Guided by the “Receiver Operating Characteristic” Curve Approach. Application to High-Throughput Docking on Metabotropic Glutamate Receptor Subtype 4

Journal of Medicinal Chemistry, 2005

The "receiver operating characteristic" (ROC) curve method is a well-recognized metric used as an... more The "receiver operating characteristic" (ROC) curve method is a well-recognized metric used as an objective way to evaluate the ability of a given test to discriminate between two populations. This facilitates decision-making in a plethora of fields in which a wrong judgment may have serious consequences including clinical diagnosis, public safety, travel security, and economic strategies. When virtual screening is used to speed-up the drug discovery process in pharmaceutical research, taking the right decision upon selecting or discarding a molecule prior to in vitro evaluation is of paramount importance. Characterizing both the ability of a virtual screening workflow to select active molecules and the ability to discard inactive ones, the ROC curve approach is well suited for this critical decision gate. As a case study, the first virtual screening workflow focused on metabotropic glutamate receptor subtype 4 (mGlu4R) agonists is reported here. Six compounds out of 38 selected and tested in vitro were shown to have agonist activity on this target of therapeutic interest.

Research paper thumbnail of High-Potency Olfactory Receptor Agonists Discovered by Virtual High-Throughput Screening: Molecular Probes for Receptor Structure and Olfactory Function

Neuron, 2008

The detection of diverse chemical structures by the vertebrate olfactory system is accomplished b... more The detection of diverse chemical structures by the vertebrate olfactory system is accomplished by the recognition of odorous ligands by their cognate receptors. In the present study, we used computational screening to discover novel high-affinity agonists of an olfactory G protein-coupled receptor that recognizes amino acid ligands. Functional testing of the top candidates validated several agonists with potencies higher than any of the receptor&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s known natural ligands. Computational modeling revealed molecular interactions involved in ligand binding and further highlighted interactions that have been conserved in evolutionarily divergent amino acid receptors. Significantly, the top compounds display robust activities as odorants in vivo and include a natural product that may be used to signal the presence of bacteria in the environment. Our virtual screening approach should be applicable to the identification of new bioactive molecules for probing the structure of chemosensory receptors and the function of chemosensory systems in vivo.

Research paper thumbnail of Design and synthesis of APTCs (aminopyrrolidinetricarboxylic acids): Identification of a new group III metabotropic glutamate receptor selective agonist

Bioorganic & Medicinal Chemistry Letters, 2006

A new family of mGlu receptor orthosteric ligands called APTCs was designed and synthesized using... more A new family of mGlu receptor orthosteric ligands called APTCs was designed and synthesized using a parallel chemistry approach. Amongst 65 molecules tested on mGlu4, mGlu6 and mGlu8 subtypes, (2S,4S)-4-amino-1-[(E)-3-carboxyacryloyl]pyrrolidine-2,4-dicarboxylic acid (8a06-FP0429) has been shown to be a full mGlu4 agonist and a partial mGlu8 agonist. In addition, 8a06 was shown to be selective versus group I and II mGlu subtypes. A possible explanation for this efficacy difference is proposed by docking experiment performed with molecular model of the receptor.

Research paper thumbnail of Neuron Report High-Potency Olfactory Receptor Agonists Discovered by Virtual High-Throughput Screening: Molecular Probes for Receptor Structure and Olfactory Function

The detection of diverse chemical structures by the vertebrate olfactory system is accomplished b... more The detection of diverse chemical structures by the vertebrate olfactory system is accomplished by the recognition of odorous ligands by their cognate receptors. In the present study, we used computational screening to discover novel high-affinity agonists of an olfactory G protein-coupled receptor that recognizes amino acid ligands. Functional testing of the top candidates validated several agonists with potencies higher than any of the receptor's known natural ligands. Computational modeling revealed molecular interactions involved in ligand binding and further highlighted interactions that have been conserved in evolutionarily divergent amino acid receptors. Significantly, the top compounds display robust activities as odorants in vivo and include a natural product that may be used to signal the presence of bacteria in the environment. Our virtual screening approach should be applicable to the identification of new bioactive molecules for probing the structure of chemosensory receptors and the function of chemosensory systems in vivo.

Research paper thumbnail of Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach

Bioorganic & Medicinal Chemistry Letters, 2010

We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold... more We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.

Research paper thumbnail of Supplemental Data High-Potency Olfactory Receptor Agonists Discovered by Virtual High-Throughput Screening: Molecular Probes for Receptor Structure and Olfactory Function

Computational protocols were designed for both ligand-based and structure-based screening workflo... more Computational protocols were designed for both ligand-based and structure-based screening workflows using the ROC curve method (Triballeau et al., 2005). Accordingly, a set of 26 active compounds identified by Speca et al. (Speca et al., 1999) (the 20 natural α-amino acids as well as agmatine, L-citrulline, L-ornithine, L-NAME, L-homoarginine and cadaverine) was divided below and above a 4 μM affinity threshold into an active and an inactive subset, respectively. This threshold corresponds to the affinity of glycine (K i = 3.9 µM) (Speca et al., 1999), which lacks a side chain capable of interacting with distal binding pocket residues (Luu et al., 2004). Thus, for any given compound, K i < 4 µM reflects stabilizing side chain interactions with the receptor, whereas K i > 4 µM reflects destabilizing side chain interactions. The ROC curve methodology allowed us to optimize parameters for both structure-based and ligand-based vHTS. Computational parameter optimization was performed iteratively by comparing the active/inactive in silico distributions with respect to the experimental data (Speca et al., 1999) and quantified by the ROC curve AUC ( ).

Research paper thumbnail of Rose Bengal analogs and vesicular glutamate transporters (VGLUTs

Bioorganic & Medicinal Chemistry, 2010

Vesicular glutamate transporters (VGLUTs) allow the loading of presynaptic glutamate vesicles and... more Vesicular glutamate transporters (VGLUTs) allow the loading of presynaptic glutamate vesicles and thus play a critical role in glutamatergic synaptic transmission. Rose Bengal (RB) is the most potent known VGLUT inhibitor (K i 25 nM); therefore we designed, synthesized and tested in brain preparations, a series of analogs based on this scaffold. We showed that among the two tautomers of RB, the carboxylic and not the lactonic form is active against VGLUTs and generated a pharmacophore model to determine the minimal structure requirements. We also tested RB specificity in other neurotransmitter uptake systems. RB proved to potently inhibit VMAT (K i 64 nM) but weakly VACHT (K i >9.7 lM) and may be a useful tool in glutamate/acetylcholine co-transmission studies.

Research paper thumbnail of Amino-Pyrrolidine Tricarboxylic Acids Give New Insight into Group III Metabotropic Glutamate Receptor Activation Mechanism

Molecular Pharmacology, 2006

Research paper thumbnail of A Virtual Screening Hit Reveals New Possibilities for Developing Group III Metabotropic Glutamate Receptor Agonists

Journal of Medicinal Chemistry, 2010

(R)-PCEP (3-amino-3-carboxypropyl-2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;a... more (R)-PCEP (3-amino-3-carboxypropyl-2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and tested on recombinant mGlu4 receptors. A large number of derivatives activated this receptor but was not able to discriminate between mGlu4 and mGlu8 receptors. The most potent ones 6 and 12 displayed an EC(50) of 1.0 +/- 0.2 microM at mGlu4R. Interestingly these agonists with longer alkyl chains revealed a new binding pocket adjacent to the glutamate binding site, which is lined with residues that differ among the mGluR subtypes and that will allow the design of more selective compounds. Additionally 6 was able to activate mGlu7 receptor with an EC(50) of 43 +/- 16 microM and is thus significantly more potent than L-AP4 (EC(50) of 249 +/- 106 microM).

Research paper thumbnail of Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists

Proceedings of The National Academy of Sciences, 2002

Ca 2؉ , pheromones, sweet taste compounds, and the main neurotransmitters glutamate and ␥-aminobu... more Ca 2؉ , pheromones, sweet taste compounds, and the main neurotransmitters glutamate and ␥-aminobutyric acid activate G proteincoupled receptors (GPCRs) that constitute the GPCR family 3. These receptors are dimers, and each subunit has a large extracellular domain called a Venus flytrap module (VFTM), where agonists bind. This module is connected to a heptahelical domain that activates G proteins. Recently, the structure of the dimer of mGlu1 VFTMs revealed two important conformational changes resulting from glutamate binding. First, agonists can stabilize a closed state of at least one VFTM in the dimer. Second, the relative orientation of the two VFTMs in the dimer is different in the presence of glutamate, such that their C-terminal ends (which are connected to the G protein-activating heptahelical domain) become closer by more than 20 Å. This latter change in orientation has been proposed to play a key role in receptor activation. To elucidate the respective role of VFTM closure and the change in orientation of the VFTMs in family 3 GPCR activation, we analyzed the mechanism of action of the mGlu8 receptor antagonists ACPT-II and MAP4. Molecular modeling studies suggest that these two compounds prevent the closure of the mGlu8 VFTM because of ionic and steric hindrance, respectively. We show here that the replacement of the residues responsible for these hindrances (Asp-309 and Tyr-227, respectively) by Ala allows ACPT-II or MAP4 to fully activate the receptors. These data are consistent with the requirement of the VFTM closure for family 3 GPCR activation. ‡ To whom reprint requests should be addressed.

Research paper thumbnail of Virtual Screening Workflow Development Guided by the “Receiver Operating Characteristic” Curve Approach. Application to High-Throughput Docking on Metabotropic Glutamate Receptor Subtype 4

Journal of Medicinal Chemistry, 2005

The "receiver operating characteristic" (ROC) curve method is a well-recognized metric used as an... more The "receiver operating characteristic" (ROC) curve method is a well-recognized metric used as an objective way to evaluate the ability of a given test to discriminate between two populations. This facilitates decision-making in a plethora of fields in which a wrong judgment may have serious consequences including clinical diagnosis, public safety, travel security, and economic strategies. When virtual screening is used to speed-up the drug discovery process in pharmaceutical research, taking the right decision upon selecting or discarding a molecule prior to in vitro evaluation is of paramount importance. Characterizing both the ability of a virtual screening workflow to select active molecules and the ability to discard inactive ones, the ROC curve approach is well suited for this critical decision gate. As a case study, the first virtual screening workflow focused on metabotropic glutamate receptor subtype 4 (mGlu4R) agonists is reported here. Six compounds out of 38 selected and tested in vitro were shown to have agonist activity on this target of therapeutic interest.

Research paper thumbnail of High-Potency Olfactory Receptor Agonists Discovered by Virtual High-Throughput Screening: Molecular Probes for Receptor Structure and Olfactory Function

Neuron, 2008

The detection of diverse chemical structures by the vertebrate olfactory system is accomplished b... more The detection of diverse chemical structures by the vertebrate olfactory system is accomplished by the recognition of odorous ligands by their cognate receptors. In the present study, we used computational screening to discover novel high-affinity agonists of an olfactory G protein-coupled receptor that recognizes amino acid ligands. Functional testing of the top candidates validated several agonists with potencies higher than any of the receptor&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s known natural ligands. Computational modeling revealed molecular interactions involved in ligand binding and further highlighted interactions that have been conserved in evolutionarily divergent amino acid receptors. Significantly, the top compounds display robust activities as odorants in vivo and include a natural product that may be used to signal the presence of bacteria in the environment. Our virtual screening approach should be applicable to the identification of new bioactive molecules for probing the structure of chemosensory receptors and the function of chemosensory systems in vivo.

Research paper thumbnail of Design and synthesis of APTCs (aminopyrrolidinetricarboxylic acids): Identification of a new group III metabotropic glutamate receptor selective agonist

Bioorganic & Medicinal Chemistry Letters, 2006

A new family of mGlu receptor orthosteric ligands called APTCs was designed and synthesized using... more A new family of mGlu receptor orthosteric ligands called APTCs was designed and synthesized using a parallel chemistry approach. Amongst 65 molecules tested on mGlu4, mGlu6 and mGlu8 subtypes, (2S,4S)-4-amino-1-[(E)-3-carboxyacryloyl]pyrrolidine-2,4-dicarboxylic acid (8a06-FP0429) has been shown to be a full mGlu4 agonist and a partial mGlu8 agonist. In addition, 8a06 was shown to be selective versus group I and II mGlu subtypes. A possible explanation for this efficacy difference is proposed by docking experiment performed with molecular model of the receptor.

Research paper thumbnail of Neuron Report High-Potency Olfactory Receptor Agonists Discovered by Virtual High-Throughput Screening: Molecular Probes for Receptor Structure and Olfactory Function

The detection of diverse chemical structures by the vertebrate olfactory system is accomplished b... more The detection of diverse chemical structures by the vertebrate olfactory system is accomplished by the recognition of odorous ligands by their cognate receptors. In the present study, we used computational screening to discover novel high-affinity agonists of an olfactory G protein-coupled receptor that recognizes amino acid ligands. Functional testing of the top candidates validated several agonists with potencies higher than any of the receptor's known natural ligands. Computational modeling revealed molecular interactions involved in ligand binding and further highlighted interactions that have been conserved in evolutionarily divergent amino acid receptors. Significantly, the top compounds display robust activities as odorants in vivo and include a natural product that may be used to signal the presence of bacteria in the environment. Our virtual screening approach should be applicable to the identification of new bioactive molecules for probing the structure of chemosensory receptors and the function of chemosensory systems in vivo.