Research on the Mechanism of Covalent Interactions in Targeted Drug Design
DOI:
https://doi.org/10.54097/aa6gh443Keywords:
Covalent interactions; Targeted drug design; Molecular mechanisms; Drug-target binding; Covalent inhibito.Abstract
Covalent interactions are one of the important intermolecular forces and play a significant role in the design of targeted drugs. This article provides a detailed account of the role covalent interactions play in drug-target binding and the thermodynamic and kinetic characteristics of covalent bond formation. By reviewing the relevant literature and combining with theoretical analysis, the differences in pharmacodynamics and pharmacokinetics between covalent inhibitors and traditional non-covalent inhibitors were compared. The results showed that covalent interactions could significantly enhance the binding affinity and specificity of the drug to the target protein, thereby prolonging the drug's action time and reducing the number of dosing times. And because the covalent bond is irreversible, it can avoid conformational changes of the target protein and competitive inhibition, and has great advantages in tumor treatment, etc. However, covalent drugs can also bring about problems such as off-target toxicity and immunogenicity. This article also summarizes several currently successful covalent targeted drugs, such as afatinib, osimertinib and other EGFR covalent inhibitors, and summarizes their design ideas and improvement schemes. Some design principles and development directions of covalent drugs were proposed in terms of the selection of reactive groups, the design of linkers, the properties of target amino acid residues, etc. The findings suggest that the rational use of covalent interactions can significantly increase the success rate of drug design, which is of great significance for the development of highly effective and low-toxicity targeted therapeutic drugs.
Downloads
References
[1] Ho Ying Huang, Sharon Pinus, Xiaocong Zhang, Guanyu Wang, Mathilde Broquiere, Richard Boulon, Andres M. Rueda, Yaouba Souaibou, Solene Huck, Mitchell Huot, Danielle Vlaho, Joshua Pottel, Felipe A. Venegas, Zhuoqun Lu, Christopher Hennecker, Julia Stille, Jevgenijs Tjutrins, Caitlin E. Miron, Anne Labarre, Jessica Plescia, Mihai Burai Patrascu, Steven Laplante, Laurent Chatel Chaix, Anthony K. Mittermaier, Nicolas Moitessier. Integration of computational and experimental techniques for the discovery of PLpro covalent inhibitors. When large virtual screening and rational design meet[J]. European Journal of Youdaoplaceholder0 Chemistry,2026,308
[2] Ho Ying Huang, Nicolas Moitessier. α -ketoamide-based covalent inhibitors in drug discovery: Current status and synthetic methods. [J] European journal of medicinal chemistry,2026,305
[3] Hongyan Du, Xujun Zhang, Zhenxing Wu, Odin Zhang, Shukai Gu, Mingyang Wang, Feng Zhu, Dan Li, Tingjun Hou, Peichen Pan. CovalentInDB 2.0: an updated comprehensive database for structure-based and ligand-based covalent inhibitor design and screening. [J] Nucleic acids research,2024,53(D1):
[4] Qin Zichen, Zhang Kaining, He Ping, Zhang Xue, Xie Miao, Fu Yucheng, Gu Chunmei, Zhu Yiying, Tong Aijun, Wei Hongping, Zhang Chuan, Xiang Yu. Discovering covalent inhibitors of protein-protein interactions from trillions of sulfur (VI) fluoride exchange-modified oligonucleotides. [J]. Nature chemistry, 2023,15(12):
[5] Beebe Lisa. Youdaoplaceholder0 of covalent drugs[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY,2013,246
[6] Johnson Douglas S, Weerapana Eranthie, Cravatt Benjamin F. Strategies for discovering and derisking covalent, irreversible enzyme inhibitors. [J]. Future medicinal chemistry,2010,2(6):
[7] Potashman Michele H, Duggan Mark E. Covalent modifiers: an orthogonal approach to drug design. [J]. Journal of medicinal chemistry,2009,52(5):
[8] Xu Pan. Key Target Drug Design and Mechanism of Action Based on Protein dynamics [D]. University of Chinese Academy of Sciences (Shanghai Institute of Materia Medica, Chinese Academy of Sciences), 2020.
[9] Liu Xuan. Molecular Design of Targeted Drugs Based on DTIs and Graph Neural networks [D]. Wuhan University of Science and Technology, 2024.
[10] Chen Jin; Wang Fangjun; Research progress on protein kinase-small molecule interactions based on mass spectrometry [J]. World Science and Technology - Modernization of Traditional Chinese Medicine, 2018(08): 56-63.
[11] Research progress on lysine-targeted covalent inhibitors [J]. Science China: Chemistry, 2020, 55(08): 2380-2391.
[12] Wang Aoxue, Pei Junping, Wang Guan, Ouyang Liang. Advances in covalent inhibitors targeting specific amino acids [J]. Progress in Pharmacy, 2022, 46(01):33-46.
[13] Guo Zongru. Research progress of drugs targeting covalent bonds [J]. Advances in Pharmacy, 2013, 37(11): 555-564.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Highlights in Science, Engineering and Technology
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
