Combinatorial library of asymmetric metal complexes and lead discovery for protein surface recognition

通过小的有机试剂调节蛋白质-蛋白质的相互作用仍然是一个困难的挑战，因为这种相互作用涉及的埋藏表面的大界面区域。该项目的目标是构建一个稳定的低分子量模块组装，该模块由适当的功能基团组成，可与靶向蛋白质表面互补结合。在联吡啶配体的4,4′位置合成了一系列由不同官能团组成的三联吡啶钌配合物，并利用显色底物筛选了对α -胰凝乳酶的抑制活性，从而使我们能够进行动力学酶测定。其中，含有苯丙氨酸残基的配合物在50 pM时表现出最好的抑制活性（73%），而含有赖氨酸残基的配合物则没有活性，这表明配合物与蛋白质表面附近的互补静电相互作用显著地决定了其抑制效力。为了进一步测试该策略检测蛋白质的不对称和手性环境等结构信息，我们将Fe （II）作为配体交换速率更快的中心金属，与本研究制备的一系列吡啶配体采用动态组合策略。当含glu （bpyGlu）和含lys （LysGlu）的吡啶以1:1的摩尔比与氯化铁（II）混合时，四种异构体络合物的产率有望达到1:3:3:1。当混合溶液处理凝血酶（pI=7）时，凝血酶活性的抑制效果分别优于100% Fe(bpyGlu)3和100% Fe(bpyLys)3。结果表明，不对称配合物Fe(bpyGlu) (bpyLys)2或Fe(bpyGlu)2（bpyLys）具有比对称配合物更高的抑制活性。我们相信金属配合物文库将为蛋白质表面识别的先导发现提供有用的工具，这些蛋白质表面识别应该更容易受到不对称抑制剂的影响。少

Modulation of protein-protein interactions by small organic agents still remains a difficult challenge due to the large interfacial areas of buried surface involved in such interactions. The goal of this project is to construct a stable assembly of low-molecular-weight modules that consist of appropriate functional groups for complementary binding to the targeting protein surfaces. A series of trisbipyridne ruthenium complexes consisting various functional group at 4, 4'-position of the bipyridine ligands was synthesized, and was screened for inhibition activity against alpha-chymotrypsin using the chromogenic substrate, which allows us to run the kinetic enzyme assay. Among them, the complex bearing phenylalanine residues showed the best inhibition activity (73% inhibition at 50 pM), whereas the one having cationic charged residue derived from lysines showed no activity, suggesting that the complementary electrostatic interaction in between the complex and the protein surface near the … More active site remarkably dictates the inhibition potency. For further test in this strategy to detect the protein structural information such as asymmetrical and chiral environment, we applied a dynamic combinatorial strategy using Fe (II), which can be a central metal with faster ligand exchanging rate, with the series of pyridine ligands prepared in this study. When 1:1 molar ratio of Glu-containing (bpyGlu) and Lys-containing (LysGlu) pyridines are mixed with iron(II) chloride, a mixture of four isomeric complexes is expected to yield in 1:3:3:1 ratio. When thrombin (pI=7) was treated with the mixture solution, the activity was suppressed more effectively than 100% of Fe(bpyGlu)3 or Fe(bpyLys)3, respectively. This result suggested that asymmetric complex, either Fe(bpyGlu) (bpyLys)2 or Fe(bpyGlu)2(bpyLys) possess higher inhibition activity than the corresponding symmetric complex. We believe that the metal complex library would provide a useful tool for the lead discovery for protein surface recognition, which should be more vulnerable with asymmetric inhibitors. Less