TY - JOUR

T1 - Ionotropic glutamate receptor GluA2 in complex with bicyclic pyrimidinedione-based compounds: when small compound modifications have distinct effects on binding interactions

AU - Frydenvang, Karla

AU - Pickering, Darryl S

AU - Kshirsagar, Giridhar U

AU - Chemi, Giulia

AU - Gemma, Sandra

AU - Sprogøe, Desiree

AU - Kærn, Anne Mette

AU - Brogi, Simone

AU - Campiani, Giuseppe

AU - Butini, Stefania

AU - Kastrup, Jette Sandholm

PY - 2020

Y1 - 2020

N2 - AMPA receptors comprise an important class of ionotropic glutamate receptors activated by glutamate in the central nervous system. These receptors have been shown to be involved in brain diseases, e.g. Alzheimer's disease and epilepsy. To understand the functional role of AMPA receptors at the molecular level and their potential as targets for drugs, development of tool compounds is essential. We have previously reported the synthesis of six bicyclic pyrimidinedione-based analogues of willardiine with differences limited to the pyrimidinedione-fused five-membered rings. Despite minor molecular differences, we observed >500-fold difference in binding affinity of the compounds at full-length GluA2. Here, we report binding affinities and the binding mode of these compounds at the ligand-binding domain of GluA2 using X-ray crystallography. The structures revealed similar binding modes, but with distinct differences in the interaction between GluA2 and the compounds. The methylene (2) and sulfur (3) containing compounds showed the greatest binding affinities. Changing the dihydrothiophene (3) into pyrrolidine (4), N-methyl pyrrolidine (5) or dihydrofuran (6) induced flexibility in the position of a binding-site water molecule and changes in the hydrogen-bonding network between compound, water and GluA2. This might be essential for explaining the reduced binding affinity of these compounds. The weakest binding affinity was observed when the aliphatic oxygen containing dihydrofuran (6) was changed into an aromatic furan system (7). Molecular docking studies revealed two possible orientations of 7, whereas only one binding mode was observed for the other analogues. This could likely contribute to the weakest binding affinity of 7 at GluA2.

AB - AMPA receptors comprise an important class of ionotropic glutamate receptors activated by glutamate in the central nervous system. These receptors have been shown to be involved in brain diseases, e.g. Alzheimer's disease and epilepsy. To understand the functional role of AMPA receptors at the molecular level and their potential as targets for drugs, development of tool compounds is essential. We have previously reported the synthesis of six bicyclic pyrimidinedione-based analogues of willardiine with differences limited to the pyrimidinedione-fused five-membered rings. Despite minor molecular differences, we observed >500-fold difference in binding affinity of the compounds at full-length GluA2. Here, we report binding affinities and the binding mode of these compounds at the ligand-binding domain of GluA2 using X-ray crystallography. The structures revealed similar binding modes, but with distinct differences in the interaction between GluA2 and the compounds. The methylene (2) and sulfur (3) containing compounds showed the greatest binding affinities. Changing the dihydrothiophene (3) into pyrrolidine (4), N-methyl pyrrolidine (5) or dihydrofuran (6) induced flexibility in the position of a binding-site water molecule and changes in the hydrogen-bonding network between compound, water and GluA2. This might be essential for explaining the reduced binding affinity of these compounds. The weakest binding affinity was observed when the aliphatic oxygen containing dihydrofuran (6) was changed into an aromatic furan system (7). Molecular docking studies revealed two possible orientations of 7, whereas only one binding mode was observed for the other analogues. This could likely contribute to the weakest binding affinity of 7 at GluA2.

U2 - 10.1021/acschemneuro.0c00195

DO - 10.1021/acschemneuro.0c00195

M3 - Journal article

C2 - 32437601

VL - 11

SP - 1791

EP - 1800

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 12

ER -