Abstract：
Voltage-gated sodium channels (VGSCs, or Nav) are important determinants of action potential generation and propagation. Efforts are underway to develop medicines targeting different channel subtypes for the treatment of related channelopathies. However, a high degree of conservation across its nine subtypes could lead to the off-target adverse effects on skeletal and cardiac muscles due to acting on primary skeletal muscle sodium channel Nav1.4 and cardiac muscle sodium channel Nav1.5, respectively. For a long evolutionary process, some peptide toxins from venoms have been found to be highly potent yet selective on ion channel subtypes and, therefore, hold the promising potential to be developed into therapeutic agents. In this research, all-atom molecular dynamic methods were used to elucidate the selective mechanisms of an analgesic-antitumor β-scorpion toxin (AGAP) with human Nav1.4 and Nav1.5 in order to unravel the primary reason for the production of its adverse reactions on the skeletal and cardiac muscles. Our results suggest that the rational distribution of residues with ring structures near position 38 and positive residues in the C-terminal on AGAP are critical factors to ensure its analgesic efficacy. Moreover, the substitution for residues with benzene is beneficial to reduce its side effects.
摘要：
电压门控钠通道(VGSCs，或Nav）是动作电位产生和传播的重要决定因素。正在努力开发针对不同通道亚型的药物，以治疗相关的通道病。然而,其9种亚型的高度保守性可能导致对骨骼肌和心肌的脱靶不良影响,这是因为它们分别作用于原发性骨骼肌钠通道Nav1.4和心肌钠通道Nav1.5.在漫长的进化过程中，已经发现来自毒液的一些肽毒素对离子通道亚型具有高度的效力和选择性，因此,拥有发展成为治疗剂的有希望的潜力。在这项研究中,使用全原子分子动力学方法阐明人Nav1.4和Nav1.5的镇痛-抗肿瘤β-蝎子毒素(AGAP)的选择性机制,以阐明其对骨骼肌和心肌产生不良反应的主要原因.我们的结果表明，在AGAP上38位附近具有环状结构的残基的合理分布和C末端的阳性残基是确保其镇痛效果的关键因素。此外，用苯代替残留物有利于减少其副作用。
