Molecular Structure of Cell Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
Crick-GSK Biomedical LinkLabs, GSK, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. Electronic address: https://twitter.com/Jake_T_Bush.
Curr Opin Struct Biol. 2024 Jun;86:102809. doi: 10.1016/j.sbi.2024.102809. Epub 2024 Mar 29.
An important consideration in drug discovery is the prioritization of tractable protein targets that are not only amenable to binding small molecules, but also alter disease biology in response to small molecule binding. Covalent fragment-based drug discovery has emerged as a powerful approach to aid in the identification of such protein targets. The application of irreversible binding mechanisms enables the identification of fragment hits for challenging-to-target proteins, allows proteome-wide screening in a cellular context, and makes it possible to determine functional effects with modestly potent ligands without the requirement for extensive compound optimization. Here, we provide an overview of recent approaches to covalent fragment-based screening and discuss how these have been applied to establish the tractability of unexplored binding sites on protein targets.
在药物发现中，一个重要的考虑因素是优先选择可成药的蛋白靶标，这些靶标不仅易于与小分子结合，而且在与小分子结合后能改变疾病的生物学特性。基于共价片段的药物发现已成为一种有力的方法，可帮助识别此类蛋白靶标。不可逆结合机制的应用可识别具有挑战性的靶蛋白的片段命中，允许在细胞环境中进行全蛋白质组筛选，并使人们有可能在无需进行大量化合物优化的情况下，使用效力适中的配体来确定功能效应。在这里，我们概述了最近用于基于共价片段的筛选的方法，并讨论了这些方法如何被应用于确定蛋白靶标上未探索的结合位点的可成药性。
