Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON, M5G 1L7, Canada.
Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON, M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Drug Discov Today. 2020 Mar;25(3):561-567. doi: 10.1016/j.drudis.2020.02.006. Epub 2020 Feb 19.
International efforts are underway to develop chemical probes for specific protein families, and a 'Target 2035' call to expand these efforts towards a comprehensive chemical coverage of the druggable human genome was recently announced. But what is the druggable genome? Here, we systematically review structures of proteins bound to drug-like ligands available from the Protein Data Bank (PDB) and use ligand desolvation upon binding as a druggability metric to draw a landscape of the human druggable genome. The vast majority of druggable protein families, including some highly populated and disease-associated families, are almost orphan of small-molecule ligands. We propose a list of 46 druggable domains representing 3440 human proteins that could be the focus of large chemical probe discovery efforts.
国际上正在努力开发针对特定蛋白质家族的化学探针，最近宣布了一项“2035 年目标”呼吁，呼吁将这些努力扩大到对可成药人类基因组进行全面的化学覆盖。但是，可成药基因组是什么？在这里，我们系统地综述了来自蛋白质数据库（PDB）中与药物样配体结合的蛋白质结构，并使用结合时配体去溶剂化作为成药性度量标准，描绘了人类可成药基因组的全景图。绝大多数可成药的蛋白质家族，包括一些高度流行和与疾病相关的家族，几乎没有小分子配体。我们提出了一个包含 46 个可成药结构域的列表，代表 3440 个人类蛋白质，这些结构域可能成为大型化学探针发现努力的重点。
