The Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
ACS Comb Sci. 2011 May 9;13(3):205-8. doi: 10.1021/co200038g. Epub 2011 Apr 21.
Disulfide exchange screening is a method for evaluating the binding of small molecule fragments to proteins that have at least one accessible cysteine. While operationally simple, it does require a large library of small fragment molecules bearing disulfide-containing side chains. These specialized fragments are not available commercially and this has limited the adoption of the method. We report here a convenient one-pot procedure that enables facile preparation of disulfide screening fragments while also producing less of an environmental impact. The new synthetic method involves the initial formation of symmetric disulfides, followed by a disulfide exchange reaction in which the symmetrical dimer is converted into the final screening fragment by introduction of a solubilizing 'cap'. The method is amenable to parallel synthetic methods and can be carried out in air without the need for the specialized equipment typically required for performing organic synthesis.
二硫键交换筛选是一种评估小分子片段与至少含有一个可及半胱氨酸的蛋白质结合的方法。虽然操作简单，但它确实需要一个包含含二硫键侧链的小分子片段的大型文库。这些专门的片段无法在商业上获得，这限制了该方法的采用。我们在这里报告了一种方便的一锅法，能够方便地制备二硫键筛选片段，同时减少对环境的影响。新的合成方法涉及对称二硫键的初始形成，然后是二硫键交换反应，其中通过引入可溶“帽”将对称二聚体转化为最终的筛选片段。该方法适用于平行合成方法，并且可以在空气中进行，而无需进行有机合成通常所需的特殊设备。
