Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties

Hao, Yihang; Wang, Haofan; Liu, Xianggen; Gai, Wenrui; Hu, Shilong; Liu, Wencheng; Miao, Zhuang; Gan, Yu; Yu, Xianghua; Shi, Rongjia; Tan, Yongzhen; Kang, Ting; Hai, Ao; Zhao, Yi; Fu, Yihang; Tang, Yaling; Ye, Ling; Liu, Jin; Liang, Xinhua; Ke, Bowen

doi:10.1016/j.apsb.2024.01.019

Acta Pharmaceutica Sinica B

2024

DOI: 10.1016/j.apsb.2024.01.019

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Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties

Yihang Hao,

Haofan Wang,

Xianggen Liu

et al.

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Optimizing Nav1.7‐Targeted Analgesics: Revealing Off‐Target Effects of Spider Venom‐Derived Peptide Toxins and Engineering Strategies for Improvement

Luo,

Zhou,

et al. 2024

Advanced Science

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The inhibition of Nav1.7 is a promising strategy for the development of analgesic treatments. Spider venom‐derived peptide toxins are recognized as significant sources of Nav1.7 inhibitors. However, their development has been impeded by limited selectivity. In this study, eight peptide toxins from three distinct spider venom Nav channel families demonstrated robust inhibition of hNav1.7, rKv4.2, and rKv4.3 (rKv4.2/4.3) currents, exhibiting a similar mode of action. The analysis of structure and function relationship revealed a significant overlap in the pharmacophore responsible for inhibiting hNav1.7 and rKv4.2 by HNTX‐III, although Lys25 seems to play a more pivotal role in the inhibition of rKv4.2/4.3. Pharmacophore‐guided rational design is employed for the development of an mGpTx1 analogue, mGpTx1‐SA, which retains its inhibition of hNav1.7 while significantly reducing its inhibition of rKv4.2/4.3 and eliminating cardiotoxicity. Moreover, mGpTx1‐SA demonstrates potent analgesic effects in both inflammatory and neuropathic pain models, accompanied by an improved in vivo safety profile. The results suggest that off‐target inhibition of rKv4.2/4.3 by specific spider peptide toxins targeting hNav1.7 may arise from a conserved binding motif. This insight promises to facilitate the design of hNav1.7‐specific analgesics, aimed at minimizing rKv4.2/4.3 inhibition and associated toxicity, thereby enhancing their suitability for therapeutic applications.

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Optimizing Nav1.7‐Targeted Analgesics: Revealing Off‐Target Effects of Spider Venom‐Derived Peptide Toxins and Engineering Strategies for Improvement

Luo,

Zhou,

et al. 2024

Advanced Science

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show abstract

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Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties

Cited by 1 publication

References 50 publications

Optimizing Nav1.7‐Targeted Analgesics: Revealing Off‐Target Effects of Spider Venom‐Derived Peptide Toxins and Engineering Strategies for Improvement

Optimizing Nav1.7‐Targeted Analgesics: Revealing Off‐Target Effects of Spider Venom‐Derived Peptide Toxins and Engineering Strategies for Improvement

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