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.

中文翻译：

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基于结构的可药物基因组视图。

国际上正在努力为特定蛋白质家族开发化学探针，最近宣布了“目标 2035”号召，以扩大这些努力，以实现对可药物人类基因组的全面化学覆盖。但什么是可成药的基因组？在这里，我们系统地审查了与蛋白质数据库 (PDB) 中可用的药物样配体结合的蛋白质的结构，并在结合时使用配体去溶剂化作为成药性指标来绘制人类可成药基因组的图景。绝大多数可成药蛋白家族，包括一些人口密集和疾病相关的家族，几乎都是小分子配体的孤儿。我们提出了代表 3440 种人类蛋白质的 46 个可成药域的列表，这些域可能是大型化学探针发现工作的重点。