Farnesyl diphosphate synthase inhibitors with unique ligand-binding geometries.
Farnesyl diphosphate synthase inhibitors with unique ligand-binding geometries.
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DOI：
10.1021/ml500528x
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发表时间：
2015-02
影响因子：
4.2
通讯作者：
Yi‐Liang Liu;R. Cao;Yang Wang;E. Oldfield
中科院分区：
文献类型：
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作者：
Yi‐Liang Liu;R. Cao;Yang Wang;E. Oldfield
法尼酯二磷酸合成酶（FPPS）是骨吸收、癌症和一些感染性疾病的重要药物靶点。在这里，我们报告了五个新的结构，其中两个具有独特的结合配体几何形状。二胺抑制剂7结合到人类FPPS靠近同丙烯基（S2）和变构（S3）位点，并延伸到一个新的位点，这里称为S4。使用双膦酸盐抑制剂8，两个分子结合到布氏锥虫的FPPS上，一个分子在烯丙基位点（S1），另一个分子靠近S2，首次观察到两个双膦酸盐分子结合到FPPS上。为了比较，我们还报道了布鲁氏体载脂蛋白fpps的结构，以及另外两种二磷酸盐结合结构（2,9）。二胺结构特别令人感兴趣，因为7可能代表了亲脂性FPPS抑制剂的新先导，而8对人类非洲锥虫病的病原体布氏体具有低微摩尔活性。
Farnesyl diphosphate synthase (FPPS) is an important drug target for bone resorption, cancer, and some infectious diseases. Here, we report five new structures including two having unique bound ligand geometries. The diamidine inhibitor 7 binds to human FPPS close to the homoallylic (S2) and allosteric (S3) sites and extends into a new site, here called S4. With the bisphosphonate inhibitor 8, two molecules bind to Trypanosoma brucei FPPS, one molecule in the allylic site (S1) and the other close to S2, the first observation of two bisphosphonate molecules bound to FPPS. We also report the structures of apo-FPPS from T. brucei, together with two more bisphosphonate-bound structures (2,9), for purposes of comparison. The diamidine structure is of particular interest because 7 could represent a new lead for lipophilic FPPS inhibitors, while 8 has low micromolar activity against T. brucei, the causative agent of human African trypanosomiasis.