Immobilized metal-ion affinity chromatography (IMAC) used to purify recombinant proteins features a resin-bound 1:1 Ni(II)-iminodiacetic acid (IDA) complex. This hemi-saturated Ni(II)-IDA system containing exchangeable sites at the metal ion is re-cast as a surrogate of a coordinatively-unsaturated metalloenzyme active site, with utility for selecting compounds with metal-binding groups from mixtures as potential metalloenzyme inhibitors. Exchanging Ni(II) for other metal ions could broaden the scope of metalloenzyme target. This work examined the performance of Cu(II)-, Fe(III)-, Ga(III)-, Ni(II)-, or Zn(II)-IMAC resins to reversibly bind experimental or clinical metalloenzyme inhibitors of Zn(II)-ACE1, Zn(II)-HDAC, Fe(II)/(III)-5-LO or Cu(II)-tyrosinase from a curated mixture (1-17). Each IMAC system gave a distinct selection profile. The Zn(II)-IMAC system selectively bound the thiol-containing Zn(II)-ACE1 inhibitors captopril and omapatrilat, and the Fe(III)-IMAC system selectively bound the Fe(II)/(III)-5-LO inhibitor licofelone, demonstrating a remarkable IMAC-metalloenzyme metal ion match. IMAC provides a simple, water-compatible platform, which could accelerate metalloenzyme inhibitor discovery.