4pyx
From Proteopedia
Crystal structure of human carbonic anhydrase isozyme II with inhibitor
Structural highlights
Disease[CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5] Function[CAH2_HUMAN] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7] Publication Abstract from PubMedHuman carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues, and its selective inhibition provides a potential target for the treatment of numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anticancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring was designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzenesulfonamide group. The bulky ortho substituents, such as cyclooctyl or even cyclododecyl groups, fit into the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound's co-crystal structure with chimeric CA IX. The strongest inhibitor of recombinant human CA IX's catalytic domain in human cells achieved an affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound that showed the best balance between affinity and selectivity bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX. Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX.,Dudutiene V, Matuliene J, Smirnov A, Timm DD, Zubriene A, Baranauskiene L, Morkunaite V, Smirnoviene J, Michailoviene V, Juozapaitiene V, Mickeviciute A, Kazokaite J, Baksyte S, Kasiliauskaite A, Jachno J, Revuckiene J, Kisonaite M, Pilipuityte V, Ivanauskaite E, Milinaviciute G, Smirnovas V, Petrikaite V, Kairys V, Petrauskas V, Norvaisas P, Linge D, Gibieza P, Capkauskaite E, Zaksauskas A, Kazlauskas E, Manakova E, Grazulis S, Ladbury JE, Matulis D J Med Chem. 2014 Nov 26;57(22):9435-46. doi: 10.1021/jm501003k. Epub 2014 Nov 10. PMID:25358084[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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