Advanced Computational Drug Discovery Unit, Institute of Innovative Research, Tokyo Institute of Technology, 4259-J3-23, Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
Education Academy of Computational Life Sciences (ACLS), Tokyo Institute of Technology, Yokohama, 226-8501, Japan.
Sci Rep. 2017 Jul 27;7(1):6666. doi: 10.1038/s41598-017-06411-9.
Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a novel anti-Chagas drug, we virtually screened 4.8 million small molecules against spermidine synthase (SpdSyn) as the target protein using our super computer "TSUBAME2.5" and conducted in vitro enzyme assays to determine the half-maximal inhibitory concentration values. We identified four hit compounds that inhibit T. cruzi SpdSyn (TcSpdSyn) by in silico and in vitro screening. We also determined the TcSpdSyn-hit compound complex structure using X-ray crystallography, which shows that the hit compound binds to the putrescine-binding site and interacts with Asp171 through a salt bridge.
克氏锥虫感染导致的恰加斯病是一种被忽视的热带病（NTD）。尽管有一些治疗药物可用，但它们的使用与严重问题相关，包括不良反应和在慢性疾病阶段的有限疗效。为了开发一种新型的抗恰加斯病药物，我们使用我们的超级计算机“TSUBAME2.5”针对精脒合酶（SpdSyn）作为靶蛋白虚拟筛选了 480 万个小分子，并进行了体外酶测定以确定半最大抑制浓度值。我们通过计算机筛选和体外筛选鉴定了四种抑制 T. cruzi SpdSyn（TcSpdSyn）的命中化合物。我们还使用 X 射线晶体学确定了 TcSpdSyn-命中化合物的复合物结构，该结构表明命中化合物结合到腐胺结合位点，并通过盐桥与 Asp171 相互作用。
