Abstract

KCNQ2 channel is one of the important members of potassium voltage-gated channel. KCNQ2 is closely related to neuronal excitatory diseases including epilepsy and neuropathic pain, and also acts as a drug target of the anti-epileptic drug, retigabine (RTG). In the past few decades, RTG has shown strong efficacy in the treatment of refractory epilepsy but has been withdrawn from clinical use due to its multiple adverse effects in clinical phase III trials. To overcome the drawbacks of RTG, several RTG analogues have been developed with different activation potency to KCNQ2. However, the detailed molecular mechanism by which these RTG analogues regulate KCNQ2 channel remains obscure. In this study, we used molecular simulations to analyse the interaction mode between the RTG analogues and KCNQ2, and to determine their molecular mechanism of action. Our data show that the van der Waals interactions, hydrophobic interactions, hydrogen bond, halogen bond, and π–π stacking work together to maintain the binding stability of the drugs in the binding pocket. On an atomic scale, the amide group in the carbamate and the amino group in the 2-aminophenyl moiety of RTG and RL648_81 are identified as key interaction sites. Our finding provides insight into the molecular mechanism by which KCNQ2 channels are regulated by RTG analogues. It also provides direct theoretical support for optimizing design of the KCNQ2 channel openers in the future, which will help treat refractory epilepsy caused by nerve excitability.

Graphic Abstract

摘要

KCNQ2通道是钾电压门控通道的重要成员之一。KCNQ2与包括癫痫和神经性疼痛在内的神经元兴奋性疾病密切相关，并且还充当抗癫痫药物瑞替加滨（RTG）的药物靶标。在过去的几十年中，RTG在治疗难治性癫痫中显示出强大的功效，但由于其在III期临床试验中的多种不良反应而被退出临床。为了克服RTG的缺点，已经开发了几种对KCNQ2具有不同激活效力的RTG类似物。但是，这些RTG类似物调节KCNQ2通道的详细分子机制仍然不清楚。在这项研究中，我们使用分子模拟来分析RTG类似物和KCNQ2之间的相互作用模式，并确定它们的分子作用机理。我们的数据表明范德华相互作用，疏水相互作用，氢键，卤素键和π-π堆积共同作用，可保持药物在结合袋中的结合稳定性。在原子尺度上，RTG和RL648_81的氨基甲酸酯中的酰胺基和2-氨基苯基部分中的氨基被鉴定为关键相互作用位点。我们的发现提供了对RTG类似物调节KCNQ2通道的分子机制的见解。它还为将来优化KCNQ2通道开放剂的设计提供了直接的理论支持，这将有助于治疗神经兴奋性引起的难治性癫痫。和π-π堆叠共同作用以保持药物在结合袋中的结合稳定性。在原子尺度上，RTG和RL648_81的氨基甲酸酯中的酰胺基和2-氨基苯基部分中的氨基被鉴定为关键相互作用位点。我们的发现提供了对RTG类似物调节KCNQ2通道的分子机制的见解。它还为将来优化KCNQ2通道开放剂的设计提供了直接的理论支持，这将有助于治疗由神经兴奋性引起的难治性癫痫。和π–π堆叠共同作用以保持药物在结合袋中的结合稳定性。在原子尺度上，RTG和RL648_81的氨基甲酸酯中的酰胺基和2-氨基苯基部分中的氨基被鉴定为关键相互作用位点。我们的发现提供了对RTG类似物调节KCNQ2通道的分子机制的见解。它还为将来优化KCNQ2通道开放剂的设计提供了直接的理论支持，这将有助于治疗由神经兴奋性引起的难治性癫痫。

图形摘要