Journal of Chemical Information and Modeling p. 3404 - 3416 (2015)
Update date:2022-09-26
Topics:
Norholm, Ann-Beth
Francotte, Pierre
Goffin, Eric
Botez, Iuliana
Danober, Laurence
Lestage, Pierre
Pirotte, Bernard
Kastrup, Jette S.
Olsen, Lars
Oostenbrink, Chris
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.
View MoreShouguang Haogang Chemical Co., Ltd.
Contact:86-0536-5672678
Address:Bohai Chemical Industrial Park,
Jintan City Mego Chemical Co., Ltd
Contact:+86-0519-82814387
Address:23# Dengguan Town, Jintan, Jiangsu Province, China
Shanghai Taibao Pharmaceutical Technology Co., Ltd
Contact:021-52217366
Address:shanghai
zhenjiang runjing high purity chemical co ltd
Contact:+86-511-83361155
Address:No.8.haixi road,international chemical park
Contact:86-574-26865651
Address:529 YuanBaoShan Road, Beilun District
Doi:10.1039/jr9560003296
(1956)Doi:10.1021/jm00127a012
(1989)Doi:10.1002/anie.200904776
(2009)Doi:10.1055/s-0030-1258768
(2010)Doi:10.1016/j.tetasy.2009.10.033
(2009)Doi:10.1016/j.tetlet.2016.01.020
(2016)