Xue Jian, Diao Jiasheng, Cai Guobin, Deng Lisheng, Zheng Baisong, Yao Yuan, Song Yongcheng
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.
ACS Med Chem Lett. 2013 Feb 14;4(2):278-282. doi: 10.1021/ml300419r.
1-Deoxy--xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against malaria in clinical trials. Based on our previous quantitative structure activity relationship (QSAR) and crystallographic studies, several novel pyridine-containing fosmidomycin derivatives were designed, synthesized and found to be highly potent inhibitors of DXR (DXR) having K values of 1.9 - 13 nM, with the best one being ~11× more active than fosmidomycin. These compounds also potently block the proliferation of multi-drug resistant with EC values as low as 170 nM. A 2.3 Å crystal structure of DXR in complex with one of the inhibitors is reported, showing the flexible loop of the protein undergoes conformational changes upon ligand binding and a hydrogen bond and favorable hydrophobic interactions between the pyridine group and DXR account for the enhanced activity.
非甲羟戊酸异戊二烯生物合成途径中的1-脱氧-D-木酮糖-5-磷酸还原异构酶（DXR）是开发抗疟药物的靶点。磷霉素是一种有效的DXR抑制剂，在临床试验中显示出对疟疾的安全性和有效性。基于我们之前的定量构效关系（QSAR）和晶体学研究，设计、合成了几种新型含吡啶的磷霉素衍生物，发现它们是DXR的高效抑制剂，其K值为1.9 - 13 nM，其中最佳的一种活性比磷霉素高约11倍。这些化合物还能有效阻断多药耐药菌的增殖，其EC值低至170 nM。报道了DXR与其中一种抑制剂复合物的2.3 Å晶体结构，显示蛋白质的柔性环在配体结合时发生构象变化，吡啶基团与DXR之间的氢键和良好的疏水相互作用导致活性增强。
