Structure-based rational design of novel hit compounds for pyruvate dehydrogenase multienzyme complex E1 components from Escherichia coli.
Structure-based rational design of novel hit compounds for pyruvate dehydrogenase multienzyme complex E1 components from Escherichia coli.
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DOI：
10.1016/j.bmc.2011.10.035
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发表时间：
2011-12
影响因子：
3.5
通讯作者：
Yanliang Ren;Junbo He;Lingling Feng;Xun Liao;Jing Jin;Yongjiang Li;Yi Cao;Jian Wan;H. He
中科院分区：
文献类型：
--
作者：
Yanliang Ren;Junbo He;Lingling Feng;Xun Liao;Jing Jin;Yongjiang Li;Yi Cao;Jian Wan;H. He
丙酮酸脱氢酶多酶复合物（PDHc） E1组分在细胞代谢中将糖酵解产物（丙酮酸）转化为乙酰辅酶a中起着关键作用，已被报道为抗微生物和除草剂的潜在靶点。本研究基于ThDP位点，采用基于结构的分子对接方法，首次设计了4种对大肠杆菌PDHc-E1具有高抑制活性的新型hit化合物。不出所料，4个化合物中化合物3a对大肠杆菌PDHc-E1的ic50值为6.88μM，是目前为止效果最好的抑制剂。为了阐明PDHc-E1活性位点与其抑制剂之间的相互作用机制，我们还进一步进行了基于对接的分子动力学模拟（MD）和基于MD的从头算片段分子轨道（FMO）计算。积极的结果表明，本研究提出的所有建模策略在未来设计具有结构多样性的PDHc-E1新型先导化合物方面都是一种令人鼓舞的方法。
Pyruvate dehydrogenase multienzyme complex (PDHc) E1 component plays a pivotal role in cellular metabolism to convert the product of glycolysis (pyruvate) to acetyl-CoA, and has been reported as a potential target for anti-microbial and herbicide. In present study, based on the thiamin diphosphate (ThDP) site, four novel hit compounds with high inhibitory activity against the PDHc-E1 from Escherichia coli were firstly designed by using structure-based molecular docking methods. As expected, among four compounds, the compound 3a is the best inhibitor by far, with IC50value of 6.88μM against PDHc-E1 from E. coli. To elucidate the interaction mechanism between the active site of PDHc-E1 and its inhibitor, the docking-based molecular dynamics simulation (MD) and MD-based ab initio fragment molecular orbital (FMO) calculations were also further performed. The positive results indicated that all modeling strategies presented in the current study most like to be an encouraging way in design of novel lead compounds with structural diversity for PDHc-E1 in the future.