In this report, we present a quantum chemical/density functional theory (DFT) study of possible zinc binding modes for five imidazole- and thiol-based ligands relevant to metzincin (MMP and ADAM) inhibitor design. The gas-phase DFT calculations show that, while the imidazole-based ligands may bind zinc in either a five-coordinate bidentate or a four-coordinate monodentate manner, the deprotonated thiolate-containing mercaptoketone and mercapto alcohol ligands are not strongly bidentate, in agreement with recently reported model complex structures. On the basis of modeling of ligand-water exchange reactions, we estimate that the free energy released upon coordination of these zinc binding groups to metzincins decreases in the order mercaptoketone > mercapto alcohol > imidazole-based. The range of binding free energies, however, is only about a few kcal/mol, in the gas phase. In addition, calculated proton dissociation energies show that the driving force for deprotonation of coordinated thiol is greater than that for either imidazole or water. In other words, the Zn-SRH moieties are generally more acidic than their or Zn-ImH or Zn-OH2 counterparts. These results suggest feasibility of imidazole-based chelating moieties as zinc binding groups in the design of MMP and ADAM inihibitors.