Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Centre of Competence in Research Chemical Biology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Nat Chem Biol. 2011 Jun;7(6):375-83. doi: 10.1038/nchembio.557. Epub 2011 Apr 17.
We introduce an approach for detection of drug-protein interactions that combines a new yeast three-hybrid screening for identification of interactions with affinity chromatography for their unambiguous validation. We applied the methodology to the profiling of clinically approved drugs, resulting in the identification of previously known and unknown drug-protein interactions. In particular, we were able to identify off-targets for erlotinib and atorvastatin, as well as an enzyme target for the anti-inflammatory drug sulfasalazine. We demonstrate that sulfasalazine and its metabolites, sulfapyridine and mesalamine, are inhibitors of the enzyme catalyzing the final step in the biosynthesis of the cofactor tetrahydrobiopterin. The interference with tetrahydrobiopterin metabolism provides an explanation for some of the beneficial and deleterious properties of sulfasalazine and furthermore suggests new and improved therapies for the drug. This work thus establishes a powerful approach for drug profiling and provides new insights in the mechanism of action of clinically approved drugs.
我们介绍了一种用于检测药物-蛋白相互作用的方法，该方法结合了一种新的酵母三杂交筛选方法用于鉴定相互作用，并用亲和层析法对其进行明确验证。我们将该方法应用于临床批准药物的分析，从而鉴定了先前已知和未知的药物-蛋白相互作用。特别地，我们能够鉴定出厄洛替尼和阿托伐他汀的非靶标，以及抗炎药物柳氮磺胺吡啶的酶靶标。我们证明柳氮磺胺吡啶及其代谢物磺胺吡啶和 5-氨基水杨酸是催化生物合成辅助因子四氢生物蝶呤的最后一步的酶的抑制剂。四氢生物蝶呤代谢的干扰为柳氮磺胺吡啶的一些有益和有害特性提供了一种解释，并且为该药物的新的和改进的治疗方法提供了思路。这项工作因此建立了一种强大的药物分析方法，并为临床批准药物的作用机制提供了新的见解。
