title: Exploring the influence of the protein environment on metal-binding pharmacophores.
abstract: The binding of a series of metal-binding pharmacophores (MBPs) related to the ligand 1-hydroxypyridine-2-(1H)-thione (1,2-HOPTO) in the active site of human carbonic anhydrase II (hCAII) has been investigated. The presence and/or position of a single methyl substituent drastically alters inhibitor potency and can result in coordination modes not observed in small-molecule model complexes. It is shown that this unexpected binding mode is the result of a steric clash between the methyl group and a highly ordered water network in the active site that is further stabilized by the formation of a hydrogen bond and favorable hydrophobic contacts. The affinity of MBPs is dependent on a large number of factors including donor atom identity, orientation, electrostatics, and van der Waals interactions. These results suggest that metal coordination by metalloenzyme inhibitors is a malleable interaction and that it is thus more appropriate to consider the metal-binding motif of these inhibitors as a pharmacophore rather than a "chelator". The rational design of inhibitors targeting metalloenzymes will benefit greatly from a deeper understanding of the interplay between the variety of forces governing the binding of MBPs to active site metal ions.
authors.affiliation: Departments of Chemistry and Biochemistry, ‡Pharmacology, and §Howard Hughes Medical Institute, University of California, San Diego , 9500 Gilman Drive, MC 0358, La Jolla, California 92093, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Martin
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Blachly
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008670:Metals / Q000378:metabolism*; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013871:Thiones / Q000737:chemistry*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D008670:Metals; D011725:Pyridines; D013871:Thiones; C008704:pyrithione; D024402:Carbonic Anhydrase II