人类内源性代谢组作为药物发现的药理学基线。
The human endogenous metabolome as a pharmacology baseline for drug discovery.
机构信息
Research Group on Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Medical Research Institute and University Pompeu Fabra, 08003 Barcelona, Catalonia, Spain.
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA; UNM Comprehensive Cancer Center, Albuquerque, NM, USA; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
出版信息
Drug Discov Today. 2019 Sep;24(9):1806-1820. doi: 10.1016/j.drudis.2019.06.007. Epub 2019 Jun 19.
We have limited understanding of the variation in in vitro affinities of drugs for their targets. An analysis of a highly curated set of 815 interactions between 566 drugs and 129 primary targets reveals that 71% of drug-target affinities have values above that of the corresponding endogenous ligand, 96% of them fitting within a range of two orders of magnitude. Our findings suggest that the evolutionary optimised affinity of endogenous ligands for their native proteins can serve as a baseline for the primary pharmacology of drugs. We show that the degree of off-target selectivity and safety risks of drugs derived from their secondary pharmacology depend very much on that baseline. Thus, we propose a new approach for estimating safety margins.
我们对药物与其靶点的体外亲和力的变化了解有限。对一组经过精心筛选的 566 种药物与 129 个主要靶点之间的 815 个相互作用进行分析，结果表明 71%的药物-靶点亲和力值高于相应的内源性配体，其中 96%的亲和力值在两个数量级的范围内。我们的研究结果表明，内源性配体与天然蛋白的进化优化亲和力可以作为药物主要药理学的基准。我们表明，药物的次要药理学衍生的药物的脱靶选择性和安全风险程度在很大程度上取决于该基准。因此，我们提出了一种估计安全裕度的新方法。
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