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

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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