Exploring the Pivotal Components Influencing the Side Effects Induced by an Analgesic-Antitumor Peptide from Scorpion Venom on Human Voltage-Gated Sodium Channels 1.4 and 1.5 through Computational Simulation

• Published in: Toxins 2022-12, Vol.15 (1), p.33
• Main Authors: Zhao, Fan, Fang, Liangyi, Wang, Qi, Ye, Qi, He, Yanan, Xu, Weizhuo, Song, Yongbo
• Format: Article
• Language: English
• Subjects: Action potential; adverse drug reaction; Amino acids; analgesic-antitumor peptide; Analgesics; Analgesics - adverse effects; Benzene; Binding sites; Cardiac muscle; Channel gating; Chemical compounds; Computer applications; Computer Simulation; Humans; Ion channels; Kinases; Molecular dynamics; Muscles; Musculoskeletal system; Mutation; Nav1.4; Nav1.5; NAV1.7 Voltage-Gated Sodium Channel; Peptides; Peptides - pharmacology; Pharmacology; Residues; Ring structures; Scorpion Venoms - chemistry; Side effects; Simulation; Skeletal muscle; Sodium; Sodium channels (voltage-gated); Spider Venoms - chemistry; subtype selectivity; Toxins; Venom; voltage-gated sodium channel; Voltage-Gated Sodium Channels
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins15010033

Voltage-gated sodium channels (VGSCs, or Na ) 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 Na 1.4 and cardiac muscle sodium channel Na 1.5, 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 Na 1.4 and Na 1.5 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.