Merck Research Laboratories, MSD, Newhouse, Lanarkshire, UK.
Bioorg Med Chem Lett. 2010 Aug 1;20(15):4507-10. doi: 10.1016/j.bmcl.2010.06.043. Epub 2010 Jun 10.
Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.
通过计算机辅助建模研究，发现了一种新的扩展的 P2/S2 相互作用。这个扩展区域可以容纳各种功能基团，如芳基和碱性胺。研究发现，嘧啶-2-腈的 N3 氮原子对于其组织蛋白酶半胱氨酸蛋白酶抑制作用至关重要。N1 氮原子也对抑制活性有贡献，但程度非常有限。提出了一种“原位双重激活”机制来解释这些结果。
