Center for Biophysics and Computational Biology,University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
J Med Chem. 2012 May 10;55(9):4367-72. doi: 10.1021/jm300208p. Epub 2012 May 1.
We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine headgroup binds in the allylic (S1) site with the side chain in S2, but in the presence of PPi and Mg(2+), the quinuclidine's cationic center interacts with PPi and three Mg(2+), mimicking a transition state involved in diphosphate ionization. With 3, there are again two structures. In one, the geranyl side chain binds to either S1 or S2 and the adamantane headgroup binds to S1. In the second, the side chain binds to S2 while the headgroup binds to S1. These results provide structural clues for the mechanism and inhibition of the head-to-head prenyl transferases and should aid future drug design.
我们报道了三种抑制剂与金黄色葡萄球菌脱水鲨烯合酶结合的 X 射线晶体结构：1（BPH-651）、2（WC-9）和 3（SQ-109）。化合物 2 以其 -SCN 基团被四个氢键供体包围的方式结合到 S2 位点。对于 1，我们报告了两种结构：在这两种结构中，喹啉啶头基团都与侧链在 S2 中的烯丙基（S1）位点结合，但在存在 PPi 和 Mg2+的情况下，喹啉啶的正电荷中心与 PPi 和三个 Mg2+相互作用，模拟涉及二磷酸离子化的过渡态。对于 3，又有两种结构。在一种结构中，香叶基侧链结合到 S1 或 S2 上，金刚烷头基团结合到 S1 上。在第二种结构中，侧链结合到 S2 上，而头基团结合到 S1 上。这些结果为从头二萜转移酶的机制和抑制提供了结构线索，并应有助于未来的药物设计。
