title: Probing the surface of human carbonic anhydrase for clues towards the design of isoform specific inhibitors.
abstract: The alpha carbonic anhydrases (α-CAs) are a group of structurally related zinc metalloenzymes that catalyze the reversible hydration of CO2 to HCO3(-). Humans have 15 different α-CAs with numerous physiological roles and expression patterns. Of these, 12 are catalytically active, and abnormal expression and activities are linked with various diseases, including glaucoma and cancer. Hence there is a need for CA isoform specific inhibitors to avoid off-target CA inhibition, but due to the high amino acid conservation of the active site and surrounding regions between each enzyme, this has proven difficult. However, residues towards the exit of the active site are variable and can be exploited to design isoform selective inhibitors. Here we discuss and characterize this region of "selective drug targetability" and how these observations can be utilized to develop isoform selective CA inhibitors.
authors: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, P.O. Box 100245, Gainesville, FL 32610, USA.
authors: Melissa A
authors: MA
authors: Pinard
authors: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, P.O. Box 100245, Gainesville, FL 32610, USA.
authors: Brian
authors: 0000-0002-5571-8058
authors: B
authors: Mahon
authors: Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, P.O. Box 100245, Gainesville, FL 32610, USA.
authors: Robert
authors: 0000-0002-2792-935X
authors: R
authors: McKenna
mesh_terms: D055162:Biocatalysis / Q000187:drug effects; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D002614:Chelating Agents; D017124:Conserved Sequence; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D010802:Phylogeny; D011485:Protein Binding / Q000187:drug effects; D012997:Solvents; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002614:Chelating Agents; D007527:Isoenzymes; D012997:Solvents; D013449:Sulfonamides; D002256:Carbonic Anhydrases