Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
Department of Internal Medicine, Translational Informatics Division, MSC09 5025, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Sci Rep. 2016 Apr 14;6:24240. doi: 10.1038/srep24240.
GLUT5, a fructose-transporting member of the facilitative glucose transporter (GLUT, SLC2) family, is a therapeutic target for diabetes and cancer but has no potent inhibitors. We virtually screened a library of 6 million chemicals onto a GLUT5 model and identified N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA) as an inhibitor of GLUT5 fructose transport in proteoliposomes. MSNBA inhibition was specific to GLUT5; this inhibitor did not affect the fructose transport of human GLUT2 or the glucose transport of human GLUT1-4 or bacterial GlcPSe. In MCF7 cells, a human breast cancer cell line, MSNBA competitively inhibited GLUT5 fructose uptake with a KI of 3.2 ± 0.4 μM. Ligand docking, mutagenesis and functional studies indicate that MSNBA binds near the active site and inhibitor discrimination involves H387 of GLUT5. Thus, MSNBA is a selective and potent inhibitor of fructose transport via GLUT5, and the first chemical probe for this transporter. Our data indicate that active site differences in GLUT members could be exploited to further enhance ligand specificity.
GLUT5 是易化葡萄糖转运体（GLUT，SLC2）家族的果糖转运成员，是糖尿病和癌症的治疗靶点，但没有有效的抑制剂。我们通过虚拟筛选了一个包含 600 万个化合物的文库，对 GLUT5 模型进行筛选，并鉴定出 N-[4-(甲基磺酰基)-2-硝基苯基]-1,3-苯并二恶唑-5-胺（MSNBA）是一种可抑制 GLUT5 果糖转运的抑制剂在脂质体中。MSNBA 抑制作用是特异针对 GLUT5 的；这种抑制剂不会影响人 GLUT2 的果糖转运或人 GLUT1-4 或细菌 GlcPSe 的葡萄糖转运。在 MCF7 细胞（一种人乳腺癌细胞系）中，MSNBA 竞争性抑制 GLUT5 果糖摄取，KI 为 3.2±0.4 μM。配体对接、突变和功能研究表明，MSNBA 结合在活性部位附近，抑制剂的识别涉及 GLUT5 的 H387。因此，MSNBA 是一种选择性和有效的 GLUT5 果糖转运抑制剂，也是该转运体的第一个化学探针。我们的数据表明，GLUT 成员的活性部位差异可以被利用来进一步增强配体的特异性。
