New techniques and strategies in drug discovery(2020–2024 update)  

作　　者：Qijie Gong Jian Song Yihui Song Kai Tang Panpan Yang Xiao Wang Min Zhao Liang Ouyang Li Rao Bin Yu Peng Zhan Saiyang Zhang Xiaojin Zhang 

机构地区：[1]Jiangsu Key Laboratory of Drug Design and Optimization,and Department of Chemistry,China Pharmaceutical University,Nanjing 211198,China [2]School of Basic Medical Sciences,Zhengzhou University,Zhengzhou 450001,China [3]School of Pharmaceutical Sciences&Key Laboratory of Advanced Drug Preparation Technologies,Zhengzhou University,Zhengzhou 450001,China [4]Department of Medicinal Chemistry,Key Laboratory of Chemical Biology(Ministry of Education),School of Pharmaceutical Sciences,Shandong University,Ji’nan 250012,China [5]State Key Laboratory of Biotherapy and Cancer Center,National Clinical Research Center for Geriatrics,West China Hospital,and Collaborative Innovation Center of Biotherapy,Sichuan University,Chengdu 610041,China [6]National Key Laboratory of Green Pesticide,Key Laboratory of Pesticide&Chemical Biology of Ministry of Education,Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis,College of Chemistry,Central China Normal University,Wuhan 430079,China [7]College of Chemistry,Pingyuan Laboratory,Zhengzhou University,Zhengzhou 450001,China

出　　处：《Chinese Chemical Letters》2025年第3期104-112,共9页中国化学快报(英文版)

基　　金：supported by grants from the National Natural Science Foundation of China(No.82273770);the Foundation for Innovative Research Groups of the National Natural Science Foundation of Sichuan Province(No.24NSFTD0051).

摘　　要：In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light on novel strategies in drug development.(a)The resurgence of covalent drugs is highlighted,focusing on the targeted covalent inhibitors(TCIs)and their role in enhancing selectivity and affinity.(b)The potential of the quantum mechanics-based computational aid drug design(CADD)tool,Cov_DOX,is introduced for predicting protein-covalent ligand binding structures and affinities.(c)The scaffolding function of proteins is proposed as a new avenue for drug design,with a focus on modulating protein-protein interactions through small molecules and proteolysis targeting chimeras(PROTACs).(d)The concept of pro-PROTACs is explored as a promising strategy for cancer therapy,combining the principles of prodrugs and PROTACs to enhance specificity and reduce toxicity.(e)The design of prodrugs through carbon-carbon bond cleavage is discussed,offering a new perspective for the activation of drugs with limited modifiable functional groups.(f)The targeting of programmed cell death pathways in cancer therapies with small molecules is reviewed,emphasizing the induction of autophagy-dependent cell death,ferroptosis,and cuproptosis.These insights collectively contribute to a deeper understanding of the dynamic landscape of drug discovery.

关 键 词：Drug discovery Covalent inhibitors Computational drug design Protein scaffolding Pro-PROTACs Programmed cell death C-C cleavage 

分 类 号：R914[医药卫生—药物化学]