Haipeng Yu, Xiaoran Wang, Xinyu Wang, Yizhen Yin

Chemistry - A European Journal

DOI:10.1002/chem.71680

Abstract

Covalent drugs have attracted increasing attention in modern drug discovery because of their prolonged target engagement, enhanced pharmacological efficacy, and potential to address traditionally challenging protein targets. The rapid development of electrophilic warhead chemistry, chemical biology methods, and high-throughput screening technologies has shifted covalent drug discovery from serendipitous identification to target-oriented and rational design. In recent years, phage display, mRNA display, and DNA-encoded library technologies have enabled the efficient de novo discovery of covalent peptides and small molecules, expanding the accessible chemical space for targeting cysteine, lysine, tyrosine, serine, and other reactive residues. Meanwhile, artificial intelligence has further accelerated covalent drug research by supporting covalent database construction, binding-site prediction, virtual screening, molecular generation, and structure-based ligand optimization. This article reviews recent advances in high-throughput strategies for targeted covalent drug discovery, with a focus on phage display, mRNA display, DNA-encoded libraries, and artificial intelligence (AI)-assisted approaches. We further discuss current challenges and future opportunities in the field and provide our perspectives on emerging directions for next-generation covalent ligand discovery.