Discovery Research, Sanofi-aventis, Bridgewater, NJ 08807, USA.
Bioorg Med Chem Lett. 2010 Mar 15;20(6):1821-4. doi: 10.1016/j.bmcl.2010.02.009. Epub 2010 Feb 6.
In the course of a fragment screening campaign by in silico docking followed by X-ray crystallography, a novel binding site for migration inhibitory factor (MIF) inhibitors was demonstrated. The site is formed by rotation of the side-chain of Tyr-36 to reveal a surface binding site in MIF that is hydrophobic and surrounded by aromatic side-chain residues. The crystal structures of two small inhibitors that bind to this site and of a quinolinone inhibitor, that spans the canonical deep pocket near Pro-1 and the new surface binding site, have been solved. These results suggest new opportunities for structure-based design of MIF inhibitors.
在通过计算机对接随后进行 X 射线晶体学的片段筛选活动中，证明了迁移抑制因子（MIF）抑制剂的一个新结合位点。该位点是通过 Tyr-36 侧链的旋转形成的，暴露出 MIF 中的一个表面结合位点，该位点是疏水性的，并被芳香族侧链残基包围。已经解决了两个结合到该位点的小分子抑制剂和一个横跨 Pro-1 附近的典型深口袋和新表面结合位点的喹啉酮抑制剂的晶体结构。这些结果为基于结构的 MIF 抑制剂设计提供了新的机会。
