Departamento de Fisiología, Edificio Arco de Ciencias Biológicas, Universidad de Concepción, Victor Lamas 1290, Concepción, Región del Bio Bio 4030000, Chile.
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States.
J Chem Inf Model. 2020 Dec 28;60(12):6634-6641. doi: 10.1021/acs.jcim.0c00943. Epub 2020 Dec 1.
Blocking the interaction between the Gβγ protein and the glycine receptor (GlyR) has emerged as a promising pharmacological strategy to treat acute alcohol intoxication by inhibiting ethanol potentiation on GlyR. M554 is a recently discovered small molecule capable of binding to Gβγ with potent and inhibitory activity. This compound has been tested as a mixture of diastereomers, and no information is available concerning the stereospecific activity of each species, which is critical to pursue efforts on lead optimization and drug development. In this work, we explored the differential activity of four M554 stereoisomers by molecular dynamics simulations and electrophysiological experiments. Our results revealed that the (,)-M554 stereoisomer is a promising lead compound that inhibits ethanol potentiation of GlyR.
阻断 Gβγ 蛋白与甘氨酸受体（GlyR）的相互作用已成为一种有前途的药理学策略，通过抑制乙醇对 GlyR 的增强作用来治疗急性酒精中毒。M554 是一种最近发现的小分子，能够与 Gβγ 结合，具有强大的 和 抑制活性。该化合物已作为非对映异构体混合物进行了测试，但对于每种物质的立体特异性活性尚无信息，这对于进行先导化合物优化和药物开发的努力至关重要。在这项工作中，我们通过分子动力学模拟和电生理实验探索了四种 M554 立体异构体的差异活性。我们的结果表明，（,）-M554 对映异构体是一种有前途的先导化合物，可抑制乙醇对 GlyR 的增强作用。
