Insights into the binding mode and functional components of the analgesic-antitumour peptide from <i>Buthus martensii</i> Karsch to human voltage-gated sodium channel 1.7 based on dynamic simulation analysis

Zhao, Fan; Wang, Jinlong; Ming, Hong-Yan; Zhang, Yanan; Dun, Ying-Qiao; Zhang, Jinghai; Song, Yongbo

doi:10.1080/07391102.2019.1620126

Cited by 9 publications

(8 citation statements)

References 39 publications

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“…Residues on the β-turn also represent another set of essential components that ensure the biological activity of the ligand. Those results were also in agreement with our previous MD simulation results, where the residue W38 of AGAP exerted a crucial influence on the formation of IS1 and IS2 [53].…”

Section: Discussionsupporting

confidence: 93%

Scorpion Neurotoxin Syb-prII-1 Exerts Analgesic Effect through Nav1.8 Channel and MAPKs Pathway

Bai

Song

Cao

et al. 2022

IJMS

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Trigeminal neuralgia (TN) is a common type of peripheral neuralgia in clinical practice, which is usually difficult to cure. Common analgesic drugs are difficult for achieving the desired analgesic effect. Syb-prII-1 is a β-type scorpion neurotoxin isolated from the scorpion venom of Buthus martensi Karsch (BmK). It has an important influence on the voltage-gated sodium channel (VGSCs), especially closely related to Nav1.8 and Nav1.9. To explore whether Syb-prII-1 has a good analgesic effect on TN, we established the Sprague Dawley (SD) rats’ chronic constriction injury of the infraorbital nerve (IoN-CCI) model. Behavioral, electrophysiological, Western blot, and other methods were used to verify the model. It was found that Syb-prII-1 could significantly relieve the pain behavior of IoN-CCI rats. After Syb-prII-1 was given, the phosphorylation level of the mitogen-activated protein kinases (MAPKs) pathway showed a dose-dependent decrease after IoN-CCI injury. Moreover, Syb-prII-1(4.0 mg/kg) could significantly change the steady-state activation and inactivation curves of Nav1.8. The steady-state activation and inactivation curves of Nav1.9 were similar to those of Nav1.8, but there was no significant difference. It was speculated that it might play an auxiliary role. The binding mode, critical residues, and specific interaction type of Syb-prII-1 and VSD2rNav1.8 were clarified with computational simulation methods. Our results indicated that Syb-prII-1 could provide a potential treatment for TN by acting on the Nav1.8 target.

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Section: Discussionsupporting

confidence: 93%

Scorpion Neurotoxin Syb-prII-1 Exerts Analgesic Effect through Nav1.8 Channel and MAPKs Pathway

Bai

Song

Cao

et al. 2022

IJMS

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“…Combined with our previous study [ 32 ] and this research, two major factors are highly related to the selectivity of AGAP and its mutants to hNa v 1.4, hNa v 1.5, and hNa v 1.7. First, there are progressive dissimilarities in the 3D structures of AGAP bound, in which VSD2 hNav1.7 is the narrowest, VSD2 hNav1.5 is wider, and VSD2 hNav1.4 is the widest.…”

Section: Discussionsupporting

confidence: 77%

“…To date, there has not been enough evidence to provide a panoramic mechanistic understanding of how AGAP interacts with different VGSC subtypes. In light of our previous results on the binding modes of AGAP and hNa v 1.7 [ 32 ], we herein elucidated the detailed mechanism of AGAP mutants with hNa v 1.4 and hNa v 1.5 through dynamic simulations, revealing the reason why the mutation of one single amino acid can bring about the remarkable alteration of subtype selectivity. We believe these findings are not only beneficial to avoid toxicity to the muscles and myocardium but also helpful to promote progress in developing safer and more effective treatments aimed at VGSC subtypes.…”

Section: Introductionmentioning

confidence: 90%

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

Zhao

Fang

Wang

et al. 2022

Toxins

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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.

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“…My proposal suggests looking into toxins being studied more seriously as models for analgesic medications and chronic pain treatments. The set of toxins used in this work are those of 10 from various kinds of animals: 1 Centipede, 2 Tarantulas, 1 Cone snail, 3 Spiders, 1 Pufferfish, and 2 scorpions that were selected for means of diversity [31][32][33][34][35][36][37][38][39][40]. This said diversity was an important factor in deciding which animals were included to eliminate as much overlap as possible, assuming that too many of the same species or kind of animal would have made it all the more difficult to pinpoint what exactly the inhibiting factors of the venoms were.…”

Section: Discussionmentioning

confidence: 99%

Exploring Venom Toxins as Molecular Models for Chronic Pain Treatment

Shahriyar

Chaim

2022

J Stud Res

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The purpose of this project is to propose venomous animal toxins as molecular models for pain medication. Chronic pain is a prevalent health problem among the general population, and current pharmacological treatments are oftentimes ineffective or limited due to undesirable side-effects. This project explores the role of specific Voltage- Gated Sodium Channels, such as Sodium Channel 1.7 (NaV 1.7), in setting the stage for proposing analgesics with binding properties in peripheral pain-sensing neurons. Sodium Channels, notably NaV 1.7, play a major role in human pain signaling pathways that propagate action potentials in excitable cells. By inhibiting and blocking them, analgesic effects are known to be achievable. Through means of bioinformatic tools, we explore amino acid sequence alignments, Motif scans, tertiary structure modeling, and molecular docking of venomous animal toxins for in-silico new drug discovery research. Cysteine residues in toxins were reviewed as a possible link between acting upon the receptor and their analgesic effects. This led to the questioning of cysteine's role in the search for potential antagonists of NaV 1.7. Eventually, the attempt for a further investigation prompted the consideration for molecular docking between selected toxins and the receptor, aiming to seize chronic pain.

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Insights into the binding mode and functional components of the analgesic-antitumour peptide from Buthus martensii Karsch to human voltage-gated sodium channel 1.7 based on dynamic simulation analysis

Cited by 9 publications

References 39 publications

Scorpion Neurotoxin Syb-prII-1 Exerts Analgesic Effect through Nav1.8 Channel and MAPKs Pathway

Scorpion Neurotoxin Syb-prII-1 Exerts Analgesic Effect through Nav1.8 Channel and MAPKs Pathway

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

Exploring Venom Toxins as Molecular Models for Chronic Pain Treatment

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