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

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外文摘要：Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmaco-phores within a single-molecule framework.To address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a well-known local anesthetic.DeepSA integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound generation.This framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent constraints.Through a sequence of local editing to navigate the molecular space,DeepSA successfully identified AT-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models.Mechanistic insights into AT-17 revealed its dual mode of action:selective inhibition of Nav1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway.These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.

外文关键词：

Multifunctional drugsDeep simulated annealingMolecule generationArticaine derivativesAI-enhanced drug discovery

作者：

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

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作者单位：

State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases,West China Hospital of Stomatology,Sichuan University,Chengdu 610041,China

College of Computer Science,Sichuan University,Chengdu 610065,China

Department of Anesthesiology,Laboratory of Anesthesia and Critical Care Medicine,National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology,Frontiers Science Center for Disease-Related Molecular Network,West China Hospital,Sichuan University,Chengdu 610041,China

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaResearch and Develop Program,West China Hospital of Stomatology Sichuan University,China1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,China1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,ChinaClinical Research Innovation Project,West China Hospital,Sichuan University,ChinaScience and Technology Major Project of Tibetan Autonomous Region of China,ChinaSichuan Science and Technology Program,China

项目编号：

82273784ChinaRD-03-202004ZYYC21002ZYGD230252019HXCX006XZ202201ZD0001G2023ZYD0168

出版年：

2024

DOI：

10.1016/j.apsb.2024.01.019

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(7)