Innovative design and potential applications of covalent strategy in drug discovery.

Jifa Zhang, Wen Liao, Yang Lu, Dan Zhang, Tianyong Tang, Jiaxiang Luo

Journal: European journal of medicinal chemistry 2025;284():117202

PMID: 39756145

Full Text on Elsevier Science View on PubMed

Abstract

Covalent inhibitors provide persistent inhibition while maintaining excellent selectivity and efficacy by creating stable covalent connections with specific amino acids in target proteins. This technique enables the precise inhibition of previously undruggable targets, lowering the frequency of administration and potentially bypassing drug resistance. Because of these advantages, covalent inhibitors have tremendous potential in treating cancer, inflammation, and infectious illnesses, making them extremely important in modern pharmacological research. Covalent inhibitors targeting EGFR, BTK, and KRAS (G12X), which overcome drug resistance and off-target, non-"medicinal" difficulties, as well as covalent inhibitors targeting SARS-CoV-2 M, have paved the way for the development of new antiviral medicines. Furthermore, the use of covalent methods in drug discovery procedures, such as covalent PROTACs, covalent molecular gels, covalent probes, CoLDR, and Dual-targeted covalent inhibitors, preserves these tactics' inherent features while incorporating the advantages of covalent inhibitors. This synthesis opens up new therapeutic opportunities. This review comprehensively examines the use of covalent techniques in drug discovery, emphasizing their transformational potential for future drug development.

Address: Department of Neurology, Laboratory of Neuro-system and Multimorbidity, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.; College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, China.; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].; Department of Neurology, Laboratory of Neuro-system and Multimorbidity, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].

DOI: 10.1016/j.ejmech.2024.117202

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MeSH Terms: Humans, Drug Discovery, SARS-CoV-2, Antiviral Agents, Drug Design, COVID-19 Drug Treatment, ErbB Receptors, Protein Kinase Inhibitors, Agammaglobulinaemia Tyrosine Kinase