Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors

摘要: The X-ray crystal structure of the adduct between zinc metalloenzyme carbonic anhydrase II (CA, EC 4.2.1.1) with recently discovered natural product coumarin derivative 6-(1S-hydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one showed hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative, and not parent coumarin, bound within enzyme active site. inhibitor exhibits an extended, two-arm conformation that effectively plugs entrance to site no interactions catalytically crucial ion. is sandwiched Phe131, which it makes edge-to-face stacking, Asn67/Glu238sym, several polar hydrogen bonding interactions. This unusual binding mode, molecule metal ion previously unobserved for this class presents new opportunity future drug design campaigns target mode inhibition differs substantially from classical inhibitors such as clinically used sulfonamides sulfamates. Several structurally simple scaffolds were also shown inhibit all 13 mammalian CA isoforms, constants ranging nanomolar millimolar. time dependent, maximum being observed after 6 h.