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J Med Chem. 1994 Jun 24;37(13):2100-5.

Identification of two hydrophobic patches in the active-site cavity of human carbonic anhydrase II by solution-phase and solid-state studies and their use in the development of tight-binding inhibitors.

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Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138.


This paper describes inhibitors for human carbonic anhydrase II (HCAII, EC that bind with nanomolar dissociation constants. These inhibitors were developed by exploiting interactions with hydrophobic "patches" in the lip of the active site of this enzyme. These patches are molecular surfaces presented by a phenylalanine on one face of the active-site cleft (Phe-131) and three adjacent hydrophobic residues on the opposite face (Leu-198 and Pro-201/202). Comparison of the affinities of molecules that can occupy either one or both of the two sites indicates that these hydrophobic interactions can contribute factors of 10(2)-10(3) to binding constants and that the strength of the interaction is relatively insensitive to the structure of the hydrophobic ligand. One of these inhibitors, the competitive inhibitor N-[N-[N-(4-sulfamoylbenzoyl)phenylglycyl]glycyl]glycine benzyl ester (17), has been studied by X-ray crystallographic methods in its complex with HCAII at 1.9-A resolution. The geometry of binding of the arylsulfonamide group of 17 is similar to geometries observed in other HCAII-arylsulfonamide complexes. The aromatic side chain of the phenylglycine residue of the inhibitor is inferred to pack against the hydrophobic Phe-131 face, and this interaction "steers" the peptide backbone of the inhibitor toward a region in the HCAII active site different from that occupied in the related triglycyl peptide. Attempts to design inhibitors capable of binding simultaneously to Phe-131 and Leu-198/Pro-201/202 did not lead to molecules that bound more tightly than those binding to these hydrophobic sites individually.

[Indexed for MEDLINE]

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