title: Carborane-based carbonic anhydrase inhibitors: insight into CAII/CAIX specificity from a high-resolution crystal structure, modeling, and quantum chemical calculations.
abstract: 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.
authors.affiliation: 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.
authors.forename: Pavel
authors.initials: P
authors.lastname: Mader
authors.affiliation: 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.
authors.forename: Adam
authors.initials: A
authors.lastname: Pecina
authors.affiliation: 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.
authors.forename: Petr
authors.initials: P
authors.lastname: Cígler
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Lepšík
authors.affiliation: Institute of Inorganic Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Hlavní 1001, 250 68 Řež near Prague, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Šícha
authors.affiliation: 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.
authors.forename: Pavel
authors.initials: P
authors.lastname: Hobza
authors.affiliation: Institute of Inorganic Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Hlavní 1001, 250 68 Řež near Prague, Czech Republic.
authors.forename: Bohumír
authors.initials: B
authors.lastname: Grüner
authors.affiliation: 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.
authors.forename: Jindřich
authors.initials: J
authors.lastname: Fanfrlík
authors.affiliation: 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.
authors.forename: Jiří
authors.initials: J
authors.lastname: Brynda
authors.affiliation: 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.
authors.forename: Pavlína
authors.initials: P
authors.lastname: Řezáčová
mesh_terms: D001896:Boron Compounds / Q000737:chemistry* / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005998:Glycine / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011789:Quantum Theory; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D001896:Boron Compounds; D002257:Carbonic Anhydrase Inhibitors; C119788:dodecaborate; D002256:Carbonic Anhydrases; D005998:Glycine