title: Computational study of the sulfonylated amino acid hydroxamates binding to the zinc ion within the active site of carbonic anhydrase.
abstract: The B3LYP/6-311+G(d,p) method and three ONIOM extrapolation methods ONIOM (B3LYP/6-311+G(d,p): AM1); ONIOM(B3LYP/6-311+G(d,p): MNDO); ONIOM (B3LYP/6-311+G(d,p): HF/3-21G(d)) were used to characterize the complexes of Zn2+ cation with anionic sulfonylated amino acid hydroxamates (RSO2NH-AA-CON(-)OH), possessing an unsubstituted RSO2NH-amino acyl moiety. According to the R moiety we distinguish between pentafluorophenyl and 4-methoxyphenyl derivates. The amino acid hydroxamates included in the study were the Gly, Ala, and Leu derivates. Of the inhibitors investigated, the weakest zinc affinity exhibits the pentafluorophenyl derivate with Gly amino acid and the strongest affinity the 4-methoxyphenyl derivate with Leu amino acid. The inhibitors form bidentate coordination bonds with the zinc cation by means of the sulfonyl oxygen and the ionized hydroxamate nitrogen atoms, respectively. The zinc affinities computed using the B3LYP/6-311 +G(d,p)// HF/6-31 +G(d,p) method are in very good agreement with the full density functional theory (DFT) B3LYP/6-311+G(d,p)//B3LYP/6-311+G(d,p) method and this method can be adopted to model larger complexes of inhibitors with the active site of carbonic anhydrase.
authors.affiliation: Department of Pharmaceutical Chemistry, Comenius University, Odbojárov 10, SK-83232 Bratislava, Slovakia. Sille@fpharm.uniba.sk
authors.forename: Július
authors.initials: J
authors.lastname: Sille
authors.forename: Milan
authors.initials: M
authors.lastname: Remko
mesh_terms: D002256:Carbonic Anhydrases / Q000737:chemistry*; D020134:Catalytic Domain; D003198:Computer Simulation; D056831:Coordination Complexes / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry; D006877:Hydroxamic Acids / Q000737:chemistry*; D008958:Models, Molecular; D013816:Thermodynamics; D015032:Zinc / Q000737:chemistry*
chemical_list: D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D002256:Carbonic Anhydrases; D015032:Zinc