Exploring the influence of the protein environment on metal-binding pharmacophores

J Med Chem. 2014 Aug 28;57(16):7126-35. doi: 10.1021/jm500984b. Epub 2014 Aug 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carbonic Anhydrase II / antagonists & inhibitors
  • Carbonic Anhydrase II / chemistry
  • Carbonic Anhydrase II / metabolism*
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Metals / metabolism*
  • Models, Molecular
  • Pyridines / chemistry*
  • Structure-Activity Relationship
  • Thermodynamics
  • Thiones / chemistry*


  • Carbonic Anhydrase Inhibitors
  • Metals
  • Pyridines
  • Thiones
  • pyrithione
  • Carbonic Anhydrase II

Associated data

  • PDB/4Q7P
  • PDB/4Q7S
  • PDB/4Q7V
  • PDB/4Q7W
  • PDB/4Q81
  • PDB/4Q83
  • PDB/4Q87,,,
  • PDB/4Q8X
  • PDB/4Q8Y
  • PDB/4Q8Z
  • PDB/4Q99
  • PDB/4Q9Y,