Ionotropic Glutamate Receptor GluA2 in Complex with Bicyclic Pyrimidinedione-Based Compounds: When Small Compound Modifications Have Distinct Effects on Binding Interactions

Abstract

(S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)­propanoic acid (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, for example, 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, 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.

Lithocholic acid derivatives as potent modulators of the nuclear receptor RORγt

“…This difference is responsible for a decrease in the affinity of the B-compound series compared with that of the A-compound series. For this purpose, we coupled the molecular docking studies with the evaluation of DG bind , as previously described by us, 48,49 because in this way, it is possible to capture the small structural differences that inuenced the binding affinity. In general, the docking scores and the DG bind are signicantly different between the two series, indicating that the presence of hydroxyl function (compounds B1-B6) is detrimental to the affinity of this series of compounds.…”

Virtual Combinatorial Library Screening of Quinadoline B Derivatives against SARS-CoV-2 RNA-Dependent RNA Polymerase

“…For this purpose, Prime/MM-GBSA method available in Prime software (Prime release 2018, Schrödinger, LLC, New York, NY, USA, 2018) was used. This technique computes the variation between the free and complex state of both the ligand and enzyme after energy minimization [23,24].…”

Identification of novel SIRT1 activators endowed with cardioprotective profile

“…For this purpose, Prime/MM-GBSA method available in Prime software (Prime release 2018, Schrödinger, LLC, New York, NY, 2018). This technique computes the variation between the free and the complex state of both the ligand and enzyme after energy minimization [70,71].…”