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Metal-Mediated Inhibition of Escherichia c oli Methionine Aminopeptidase: Structure−Activity Relationships and Development of a Novel Scoring Function for Metal−Ligand Interactions

2005; American Chemical Society; Volume: 49; Issue: 2 Linguagem: Inglês

10.1021/jm050476z

1520-4804

Rolf Schiffmann, Alexander Neugebauer, Christian D. Klein,

Synthesis and Biological Evaluation

We report the discovery of thiabendazole as a potent inhibitor (Ki = 0.4 μM) of Escherichia coli methionine aminopeptidase (ecMetAP) and the synthesis and pharmacological evaluation of thiabendazole congeners with activity in the upper nanomolar range. Elucidation of the X-ray structure of ecMetAP in complex with thiabendazole and an unrelated inhibitor that was independently described by another group showed that that both compounds bind to an additional CoII ion at the entrance of the active site. This unexpected finding explains the inactivity of the compounds under in vivo conditions. It also allows us to discuss the structure−activity relationships of this series of compounds in a meaningful way, based upon docking runs with an auxiliary metal ion. We describe a new scoring function for the evaluation of metal-mediated inhibitor binding that, unlike the previously used scoring function implemented in the docking program, allows us to distinguish between active and inactive compounds. Finally, conclusions for the structure-based design of in vivo-active inhibitors of ecMetAP are drawn.