State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, SAR 999077, China.
Centre for Eye and Vision Research, 17W Hong Kong Science Park, Hong Kong, SAR 999077, China.
J Med Chem. 2024 Oct 10;67(19):17542-17550. doi: 10.1021/acs.jmedchem.4c01463. Epub 2024 Sep 28.
Target identification is crucial for elucidating the mechanisms of bioactive molecules in drug discovery. However, traditional methods assess compounds individually, making it challenging to efficiently examine multiple compounds in parallel, especially for structurally diverse compounds. This study reports a novel strategy called chemical genomics-facilitated chemical proteomics (CGCP) for multiplexing the target identification of bioactive small molecules. CGCP correlates compounds' perturbation of global transcription, or chemical genomic profiles, with their reactivity toward target proteins, enabling simultaneous identification of targets. We demonstrated the utility of CGCP by studying the targets of celastrol (Cel) and four other electrophilic compounds with varying levels of similarity to Cel based on their chemical genomic profiles. We identified multiple novel targets and binding sites shared by the compounds in a single experiment. CGCP enabled multiplexity and improved the efficiency of target identification for structurally distinct compounds, indicating its potential to accelerate drug discovery.
靶标鉴定对于阐明生物活性分子在药物发现中的作用机制至关重要。然而，传统方法逐个评估化合物，难以有效地并行检测多种化合物，特别是对于结构多样的化合物。本研究报道了一种称为化学基因组学辅助化学蛋白质组学（CGCP）的新策略，用于对生物活性小分子的靶标鉴定进行多重化。CGCP 将化合物对全局转录的扰动（即化学基因组图谱）与其对靶蛋白的反应性相关联，从而能够同时鉴定靶标。我们通过研究 Celastrol（Cel）和其他四种基于其化学基因组图谱在结构上与 Cel 具有不同程度相似性的亲电化合物的靶标，证明了 CGCP 的实用性。我们在单个实验中鉴定了多个新的靶标和化合物共有的结合位点。CGCP 实现了多重化并提高了结构不同的化合物的靶标鉴定效率，表明其有潜力加速药物发现。
