Krámos Balázs, Béni Zoltán, Túrós György István, Éliás Olivér, Potor Attila, Kapus Gábor László, Szabó György
Spectroscopic Research Department, Gedeon Richter Plc., Gyömrői út 19-21, Budapest 1103, Hungary.
Medicinal Chemistry Laboratory II, Gedeon Richter Plc., Gyömrői út 19-21, Budapest 1103, Hungary.
J Chem Inf Model. 2025 Jan 13;65(1):402-416. doi: 10.1021/acs.jcim.4c01431. Epub 2024 Dec 17.
The significant importance of GABA receptors in the treatment of central nervous system (CNS) disorders has been known for a long time. However, only in recent years have experimental protein structures been published that can open the door to understanding protein-ligand interactions and may effectively help the rational drug design for the future. In our previous work (Szabó, G. 2022, 65(11), 7876), where a promising selective α5-GABA negative allosteric modulator (NAM) was developed containing the 3-(4-fluorophenyl)-5-methyl-1,2-oxazole headgroup, we noticed a switch-like effect of a single nitrogen atom for the receptor function in some derivatives having a dihydro-naphthyridinone or dihydro-isoquinolinone moiety. Here, we focused on this chemotype, and a small set of compounds were designed to investigate ligand-receptor interactions experimentally and through computational methods. Elaborated compounds were tested against GABA α1 and α5 subunit-containing receptors, and binding affinities and functional activities were measured. Starting from the published experimental structure of an engineered, homopentameric, basmisanil-binding GABA receptor-like construct consisting of modified α5 subunits and an α1-containing GABA structure, we created a new model of the ligand binding site at the α5/γ2 interface. Using this model, the measured ligand affinities were able to be reproduced well by free energy perturbation (FEP) calculations. In addition, calculations were able to explain the obtained structure-activity relationships, among others, the switch-like effect of the aromatic nitrogen position in the dihydro-naphthyridinone motif for the functional character, and suggest different binding poses for the ligands presenting silent versus negative allosteric effects in this set (SAMs vs. NAMs, respectively). We believe that our results can help design α5 selective GABA negative allosteric modulators and better understand the GABA receptor.
γ-氨基丁酸（GABA）受体在治疗中枢神经系统（CNS）疾病中的重要意义早已为人所知。然而，直到近年来才发表了实验性蛋白质结构，这为理解蛋白质-配体相互作用打开了大门，并可能有效地助力未来的合理药物设计。在我们之前的工作中（Szabó, G. 2022, 65(11), 7876），开发了一种含有3-(4-氟苯基)-5-甲基-1,2-恶唑头基的有前景的选择性α5-GABA负变构调节剂（NAM），我们注意到在一些具有二氢萘啶酮或二氢异喹啉酮部分的衍生物中，单个氮原子对受体功能具有类似开关的效应。在此，我们聚焦于这种化学类型，设计了一小批化合物，通过实验和计算方法研究配体-受体相互作用。对精心设计的化合物针对含GABA α1和α5亚基的受体进行了测试，并测量了结合亲和力和功能活性。从已发表的由修饰的α5亚基和含α1的GABA结构组成的工程化同五聚体、巴米香胺结合的GABA受体样构建体的实验结构出发，我们创建了α5/γ2界面处配体结合位点的新模型。使用该模型，通过自由能微扰（FEP）计算能够很好地重现测得的配体亲和力。此外，计算能够解释所获得的构效关系，尤其是二氢萘啶酮基序中芳香氮位置对功能特性的类似开关效应，并为该组中呈现沉默与负变构效应的配体（分别为SAMs与NAMs）提出不同的结合姿势。我们相信我们的结果有助于设计α5选择性GABA负变构调节剂，并更好地理解GABA受体。
