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References listed in PDB file
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Key reference
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Title
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Enthalpy-Entropy compensation in the binding of modulators at ionotropic glutamate receptor glua2.
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Authors
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C.Krintel,
P.Francotte,
D.S.Pickering,
L.Juknaitė,
J.Pøhlsgaard,
L.Olsen,
K.Frydenvang,
E.Goffin,
B.Pirotte,
J.S.Kastrup.
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Ref.
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Biophys J, 2016,
110,
2397-2406.
[DOI no: ]
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PubMed id
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Abstract
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The 1,2,4-benzothiadiazine 1,1-dioxide type of positive allosteric modulators of
the ionotropic glutamate receptor A2 (GluA2) are promising lead compounds for
the treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators
bind in a cleft formed by the interface of two neighboring ligand binding
domains and act by stabilizing the agonist-bound open-channel conformation. The
driving forces behind the binding of these modulators can be significantly
altered with only minor substitutions to the parent molecules. In this study, we
show that changing the 7-fluorine substituent of modulators BPAM97 (2) and
BPAM344 (3) into a hydroxyl group (BPAM557 (4) and BPAM521 (5), respectively),
leads to a more favorable binding enthalpy (ΔH, kcal/mol) from -4.9 (2) and
-7.5 (3) to -6.2 (4) and -14.5 (5), but also a less favorable binding entropy
(-TΔS, kcal/mol) from -2.3 (2) and -1.3 (3) to -0.5 (4) and 4.8 (5). Thus, the
dissociation constants (Kd, μM) of 4 (11.2) and 5 (0.16) are similar to those
of 2 (5.6) and 3 (0.35). Functionally, 4 and 5 potentiated responses of 10 μM
L-glutamate at homomeric rat GluA2(Q)i receptors with EC50 values of 67.3 and
2.45 μM, respectively. The binding mode of 5 was examined with x-ray
crystallography, showing that the only change compared to that of earlier
compounds was the orientation of Ser-497 pointing toward the hydroxyl group of
5. The favorable enthalpy can be explained by the formation of a hydrogen bond
from the side-chain hydroxyl group of Ser-497 to the hydroxyl group of 5,
whereas the unfavorable entropy might be due to desolvation effects combined
with a conformational restriction of Ser-497 and 5. In summary, this study shows
a remarkable example of enthalpy-entropy compensation in drug development
accompanied with a likely explanation of the underlying structural mechanism.
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Secondary reference #1
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Title
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Synthesis, Pharmacological and structural characterization, And thermodynamic aspects of glua2-Positive allosteric modulators with a 3,4-Dihydro-2h-1,2,4-Benzothiadiazine 1,1-Dioxide scaffold.
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Authors
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A.B.Nørholm,
P.Francotte,
L.Olsen,
C.Krintel,
K.Frydenvang,
E.Goffin,
S.Challal,
L.Danober,
I.Botez-Pop,
P.Lestage,
B.Pirotte,
J.S.Kastrup.
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Ref.
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J Med Chem, 2013,
56,
8736-8745.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor glua2.
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Authors
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C.Krintel,
K.Frydenvang,
L.Olsen,
M.T.Kristensen,
O.De barrios,
P.Naur,
P.Francotte,
B.Pirotte,
M.Gajhede,
J.S.Kastrup.
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Ref.
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Biochem J, 2012,
441,
173-178.
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PubMed id
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Secondary reference #3
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Title
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Positive allosteric modulators of 2-Amino-3-(3-Hydroxy-5-Methylisoxazol-4-Yl)propionic acid receptors belonging to 4-Cyclopropyl-3,4-Dihydro-2h-1,2,4-Pyridothiadiazine dioxides and diversely chloro-Substituted 4-Cyclopropyl-3,4-Dihydro-2h-1,2,4-Benzothiadiazine 1,1-Dioxides.
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Authors
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P.Francotte,
A.B.Nørholm,
T.Deva,
L.Olsen,
K.Frydenvang,
E.Goffin,
P.Fraikin,
P.De tullio,
S.Challal,
J.Y.Thomas,
F.Iop,
C.Louis,
I.Botez-Pop,
P.Lestage,
L.Danober,
J.S.Kastrup,
B.Pirotte.
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Ref.
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J Med Chem, 2014,
57,
9539-9553.
[DOI no: ]
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PubMed id
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Secondary reference #4
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Title
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Probing the allosteric modulator binding site of glur2 with thiazide derivatives.
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Authors
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C.P.Ptak,
A.H.Ahmed,
R.E.Oswald.
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Ref.
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Biochemistry, 2009,
48,
8594-8602.
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PubMed id
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