nature20121213-4

由邓迪大学、北卡罗莱纳大学科学家领导的一个国际研究合作已经开发出一种能够设计一次靶向多个蛋白质药物的方法。新方法可用来开发药物治疗许多常见的人类疾病如糖尿病,高血压,肥胖,癌症,精神分裂症和双极性障碍。

-2012年12月13日《自然》


中文翻译


【题目】自动化设计配体的多靶点药物

【译文】 一个药物的临床疗效和安全性决定于其在蛋白质组中许多蛋白间的活性谱。 然而,设计具有特异性多靶点谱的药物是复杂其困难的。因此设计针对一些蛋白谱的药物的方法可能在药物开发中具有广阔前景。本研究描述了一种针对多药物靶点谱的配体自动设计的新方法。该方法通过一种已批准的乙酰胆碱酯酶抑制剂发展为具有特异性多药理学性质或G蛋白偶联受体的精密选择性谱的脑渗透性配体而被加以证实。总体上说,预期设计的配体的800个配体-靶点预测被实验性的测试了,其中75%被证实是正确的。我们还在体内证实了靶点交会。当需要多靶点谱以实现对其他药物靶点的选择性或一种渴望的复方药理学,该方法可能成为药物开发的有用资源。

英文原稿


[Title]: Automated design of ligands to polypharmacological profiles

[Authors]:Jérémy Besnard,1 Gian Filippo Ruda,1 Vincent Setola,2 Keren Abecassis,1 Ramona M. Rodriguiz,3 Xi-Ping Huang,2 Suzanne Norval,1 Maria F. Sassano,4 Antony I. Shin,3 Lauren A. Webster,1 Frederick R. C. Simeons,1 Laste Stojanovski,1 Annik Prat,5 Nabil G. Seidah,5 Daniel B. Constam,6 G. Richard Bickerton,1 Kevin D. Read,1 William C. Wetsel,3, 7 Ian H. Gilbert,1 Bryan L. Roth2, 4 & Andrew L. Hopkins1

[Abstract]The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand–target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.

原文地址

http://www.nature.com/nature/journal/v492/n7428/full/nature11691.html

 

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