| Abstract
| - Hydroxamic acids, known as iron chelators, have recently been widely used as a key functional group ofpotential therapeutics targeting at zinc proteinases such as matrix metalloproteinases involved in cancers andat other drug targets associated with cardiovascular diseases, AIDS, and Alzheimer's disease. However, theprotonation states of zinc-coordinated hydroxamic acids in proteins and relative affinities of hydroxamicacids for Zn2+ are still unclear due to the intricacy of the hydroxamic acid structures. Here, we report acomprehensive ab initio study of stable configurations and tautomers of neutral and deprotonated, Zn2+-coordinated acetohydroxamic acid and its N-methyl analogue in the gas-phase employing the B3LYP/6-311+G(2d,2p) method. The results suggest that both zinc-coordinated acetohydroxamic and N-methylacetohydroxamic acids exist in the oxygen-deprotonated Z-keto form with their two oxygen atoms coordinatingto zinc in proteins in which the acidic amino acid side chains serve as a proton acceptor. This conclusion isconsistent with a survey of experimentally determined protein 3D structures complexed with zinc-coordinatedhydroxamic acids documented in the Protein Data Bank. The results also suggest that the zinc affinity ofN-methylacetohydroxamic acid is 11 kcal/mol higher than that of acetohydroxamic acid and is up to 43 kcal/mol higher than those of common zinc ligands in proteins. It thus cautions the use of N-methylacetohydroxamicacid as a functional group in rational design of inhibitors for zinc proteinases, since it may interact with otherzinc proteins due to its high affinity for zinc.
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