成功药物所靶向的人类基因的定量系统水平决定因素。
Quantitative systems-level determinants of human genes targeted by successful drugs.
作者信息
Yao Lixia, Rzhetsky Andrey
机构信息
Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA.
出版信息
Genome Res. 2008 Feb;18(2):206-13. doi: 10.1101/gr.6888208. Epub 2007 Dec 14.
What makes a successful drug target? A target molecule with an appropriate (druggable) tertiary structure is a necessary but not the sufficient condition for success. Here we analyzed specific properties of human genes and proteins targeted by 919 FDA-approved drugs and identified several quantitative measures that distinguish them from other genes and proteins at a highly significant level. Compared to an average gene and its encoded protein(s), successful drug targets are more highly connected (but far from being the most highly connected), have higher betweenness values, lower entropies of tissue expression, and lower ratios of nonsynonymous to synonymous single-nucleotide polymorphisms. Furthermore, we have identified human tissues that are significantly over- or undertargeted relative to the full spectrum of genes that are active in each tissue. Our study provides quantitative guidelines that could aid in the computational screening of new drug targets in human cells.
什么造就了一个成功的药物靶点？具有合适（可成药）三级结构的靶点分子是成功的必要条件，但并非充分条件。在此，我们分析了919种FDA批准药物所靶向的人类基因和蛋白质的特定属性，并确定了几种定量指标，这些指标在高度显著水平上区分了它们与其他基因和蛋白质。与平均基因及其编码的蛋白质相比，成功的药物靶点具有更高的连接性（但远非连接性最高）、更高的中介中心性值、更低的组织表达熵以及更低的非同义与同义单核苷酸多态性比率。此外，我们还确定了相对于每个组织中活跃的所有基因而言，显著过度或不足靶向的人类组织。我们的研究提供了定量指导原则，有助于在人类细胞中对新的药物靶点进行计算筛选。
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