Carborane-based compounds are promising lead structures for development of inhibitors of carbonic anhydrases (CAs). Here, we report structural and computational analysis applicable to structure-based design of carborane compounds with selectivity toward the cancer-specific CAIX isoenzyme. We determined the crystal structure of CAII in complex with 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane at 1.0 Å resolution and used this structure to model the 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane interactions with CAIX. A virtual glycine scan revealed the contributions of individual residues to the energy of binding of 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane to CAII and CAIX, respectively.

Institute of Inorganic Chemistry Academy of Sciences of the Czech Republic v v i Hlavní 1001 250 68 Řež near Prague Czech Republic

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Vídeňská 1083 140 00 Prague 4 Czech Republic ; Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Gilead Sciences and IOCB Research Center Flemingovo nam 2 166 10 Prague 6 Czech Republic

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Vídeňská 1083 140 00 Prague 4 Czech Republic ; Structural Genomics Consortium University of Toronto Toronto ON Canada M5G 1L7

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Gilead Sciences and IOCB Research Center Flemingovo nam 2 166 10 Prague 6 Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Gilead Sciences and IOCB Research Center Flemingovo nam 2 166 10 Prague 6 Czech Republic ; Regional Center of Advanced Technologies and Materials Department of Physical Chemistry Palacký University 77146 Olomouc Czech Republic

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