A Rational Design, Synthesis, Biological Evaluation and Structure Activity Relationship Study of Novel Inhibitors against Cyanobacterial Fructose-1,6-bisphosphate Aldolase
A Rational Design, Synthesis, Biological Evaluation and Structure Activity Relationship Study of Novel Inhibitors against Cyanobacterial Fructose-1,6-bisphosphate Aldolase
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蓝藻果糖1,6-二磷酸醛缩酶新型抑制剂的合理设计、合成、生物学评价及构效关系研究
DOI：
10.1021/acs.jcim.5b00618
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发表时间：
2016
影响因子：
5.6
通讯作者：
Wan Jian
中科院分区：
文献类型：
--
作者：
Han Xinya;Zhu Xiuyun;Zhu Shuaihua;Wei Lin;Hong Zongqin;Guo Li;Chen Haifeng;Chi Bo;Liu Yan;Feng Lingling;Ren Yanliang;Wan Jian
本研究设计并优化了一系列新型马来酰亚胺衍生物，并对其对蓝藻Class II果糖-1，6-二磷酸醛缩酶（Cy-FBA-II）和集胞藻（Synechocystissp. PCC 6803进行了进一步评价。实验结果表明，在吡咯-2 ′，5 ′-二酮环上引入较大的基团（Br、Cl、CH 3或C6 H3-o-F）会降低目标化合物的Cy-FBA-II抑制活性。一般来说，大多数具有高Cy-FBA-II抑制活性的化合物在体内也表现出较高的抗集胞藻活性。PCC 6803。其中化合物10不仅表现出较高的Cy-FBA-II活性（IC_（50）= 1.7 μM），而且对集胞藻的体内活性也最高。PCC 6803（EC50= 0.6 ppm）。因此，选择化合物10作为代表性分子，通过分子对接、分子动力学模拟、ONIOM计算和酶学分析等手段，阐明了化合物10与Cy-FBA-II活性位点周围重要残基的可能相互作用，为深入了解抑制剂与Cy-FBA-II的结合模式提供了新的思路.这些结果表明，本研究所采用的设计策略很有可能成为未来寻找新型的具有高抑制活性的Cy-FBA-II先导化合物的一种很有前途的方法。酶和藻类抑制试验表明，Cy-FBA-II很可能是一个很有前途的目标设计，合成和开发新的特定的杀藻剂，以解决蓝藻有害藻华。
In the present study, a series of novel maleimide derivatives were rationally designed and optimized, and their inhibitory activities against cyanobacteria class-II fructose-1,6-bisphosphate aldolase (Cy-FBA-II) andSynechocystissp. PCC 6803 were further evaluated. The experimental results showed that the introduction of a bigger group (Br, Cl, CH3, or C6H3-o-F) on the pyrrole-2′,5′-dione ring resulted in a decrease in the Cy-FBA-II inhibitory activity of the hit compounds. Generally, most of the hit compounds with high Cy-FBA-II inhibitory activities could also exhibit high in vivo activities againstSynechocystissp. PCC 6803. Especially, compound10not only shows a high Cy-FBA-II activity (IC50= 1.7 μM) but also has the highest in vivo activity againstSynechocystissp. PCC 6803 (EC50= 0.6 ppm). Thus, compound10was selected as a representative molecule, and its probable interactions with the surrounding important residues in the active site of Cy-FBA-II were elucidated by the joint use of molecular docking, molecular dynamics simulations, ONIOM calculations, and enzymatic assays to provide new insight into the binding mode of the inhibitors and Cy-FBA-II. The positive results indicate that the design strategy used in the present study is very likely to be a promising way to find novel lead compounds with high inhibitory activities against Cy-FBA-II in the future. The enzymatic and algal inhibition assays suggest that Cy-FBA-II is very likely to be a promising target for the design, synthesis, and development of novel specific algicides to solve cyanobacterial harmful algal blooms.