Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces

Ann-Beth Nørholm; Pierre Francotte; Eric Goffin; Iuliana Botez; Laurence Danober; Pierre Lestage; Bernard Pirotte; Jette Sandholm Jensen Kastrup; Lars Olsen; Chris Oostenbrink

doi:10.1021/ci500559b

Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces

Ann-Beth Nørholm, Pierre Francotte, Eric Goffin, Iuliana Botez, Laurence Danober, Pierre Lestage, Bernard Pirotte, Jette Sandholm Jensen Kastrup, Lars Olsen, Chris Oostenbrink

16 Citations (Scopus)

Abstract

Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer's disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodynamic driving forces. Binding of 5c (7-F) and 6 (no-F) is enthalpy driven, and 5a (5-F) and 5b (6-F) are entropy driven. For 5d (8-F), both quantities were equal in size. Thermodynamic integration (TI) and one-step perturbation (OSP) were used to calculate the relative binding affinity of the modulators. The OSP calculations had a higher predictive power than those from TI, and combined with the shorter total simulation time, we found the OSP method to be more effective for this setup. Furthermore, from the molecular dynamics simulations, we extracted the enthalpies and entropies, and along with the ITC data, this suggested that the differences in binding free energies are largely explained by the direct ligand-surrounding enthalpies. Furthermore, we used the OSP setup to predict binding affinities for a series of polysubstituted fluorine compounds and monosubstituted methyl compounds and used these predictions to characterize the modulator binding pocket for this scaffold of positive allosteric modulators.

Original language	English
Journal	Journal of Chemical Information and Modeling
Volume	54
Issue number	12
Pages (from-to)	3404-16
Number of pages	13
ISSN	1549-9596
DOIs	https://doi.org/10.1021/ci500559b
Publication status	Published - 22 Dec 2014

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Nørholm, A-B., Francotte, P., Goffin, E., Botez, I., Danober, L., Lestage, P., Pirotte, B., Kastrup, J. S. J., Olsen, L., & Oostenbrink, C. (2014). Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces. Journal of Chemical Information and Modeling, 54(12), 3404-16. https://doi.org/10.1021/ci500559b

Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain : Combining Experimental and Computational Methods Unravels Differences in Driving Forces. / Nørholm, Ann-Beth; Francotte, Pierre; Goffin, Eric et al.

In: Journal of Chemical Information and Modeling, Vol. 54, No. 12, 22.12.2014, p. 3404-16.

Research output: Contribution to journal › Journal article › Research › peer-review

Nørholm, A-B, Francotte, P, Goffin, E, Botez, I, Danober, L, Lestage, P, Pirotte, B, Kastrup, JSJ, Olsen, L & Oostenbrink, C 2014, 'Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces', Journal of Chemical Information and Modeling, vol. 54, no. 12, pp. 3404-16. https://doi.org/10.1021/ci500559b

Nørholm A-B, Francotte P, Goffin E, Botez I, Danober L, Lestage P et al. Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces. Journal of Chemical Information and Modeling. 2014 Dec 22;54(12):3404-16. doi: 10.1021/ci500559b

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title = "Thermodynamic Characterization of New Positive Allosteric Modulators Binding to the Glutamate Receptor A2 Ligand-Binding Domain: Combining Experimental and Computational Methods Unravels Differences in Driving Forces",

abstract = "Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer's disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodynamic driving forces. Binding of 5c (7-F) and 6 (no-F) is enthalpy driven, and 5a (5-F) and 5b (6-F) are entropy driven. For 5d (8-F), both quantities were equal in size. Thermodynamic integration (TI) and one-step perturbation (OSP) were used to calculate the relative binding affinity of the modulators. The OSP calculations had a higher predictive power than those from TI, and combined with the shorter total simulation time, we found the OSP method to be more effective for this setup. Furthermore, from the molecular dynamics simulations, we extracted the enthalpies and entropies, and along with the ITC data, this suggested that the differences in binding free energies are largely explained by the direct ligand-surrounding enthalpies. Furthermore, we used the OSP setup to predict binding affinities for a series of polysubstituted fluorine compounds and monosubstituted methyl compounds and used these predictions to characterize the modulator binding pocket for this scaffold of positive allosteric modulators.",

author = "Ann-Beth N{\o}rholm and Pierre Francotte and Eric Goffin and Iuliana Botez and Laurence Danober and Pierre Lestage and Bernard Pirotte and Kastrup, {Jette Sandholm Jensen} and Lars Olsen and Chris Oostenbrink",

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T2 - Combining Experimental and Computational Methods Unravels Differences in Driving Forces

AU - Nørholm, Ann-Beth

AU - Francotte, Pierre

AU - Goffin, Eric

AU - Botez, Iuliana

AU - Danober, Laurence

AU - Lestage, Pierre

AU - Pirotte, Bernard

AU - Kastrup, Jette Sandholm Jensen

AU - Olsen, Lars

AU - Oostenbrink, Chris

PY - 2014/12/22

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N2 - Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer's disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodynamic driving forces. Binding of 5c (7-F) and 6 (no-F) is enthalpy driven, and 5a (5-F) and 5b (6-F) are entropy driven. For 5d (8-F), both quantities were equal in size. Thermodynamic integration (TI) and one-step perturbation (OSP) were used to calculate the relative binding affinity of the modulators. The OSP calculations had a higher predictive power than those from TI, and combined with the shorter total simulation time, we found the OSP method to be more effective for this setup. Furthermore, from the molecular dynamics simulations, we extracted the enthalpies and entropies, and along with the ITC data, this suggested that the differences in binding free energies are largely explained by the direct ligand-surrounding enthalpies. Furthermore, we used the OSP setup to predict binding affinities for a series of polysubstituted fluorine compounds and monosubstituted methyl compounds and used these predictions to characterize the modulator binding pocket for this scaffold of positive allosteric modulators.

AB - Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimer's disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodynamic driving forces. Binding of 5c (7-F) and 6 (no-F) is enthalpy driven, and 5a (5-F) and 5b (6-F) are entropy driven. For 5d (8-F), both quantities were equal in size. Thermodynamic integration (TI) and one-step perturbation (OSP) were used to calculate the relative binding affinity of the modulators. The OSP calculations had a higher predictive power than those from TI, and combined with the shorter total simulation time, we found the OSP method to be more effective for this setup. Furthermore, from the molecular dynamics simulations, we extracted the enthalpies and entropies, and along with the ITC data, this suggested that the differences in binding free energies are largely explained by the direct ligand-surrounding enthalpies. Furthermore, we used the OSP setup to predict binding affinities for a series of polysubstituted fluorine compounds and monosubstituted methyl compounds and used these predictions to characterize the modulator binding pocket for this scaffold of positive allosteric modulators.

U2 - 10.1021/ci500559b

DO - 10.1021/ci500559b

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SN - 1549-9596

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