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Published on: January 16, 2021
Carborane-based carbonic anhydrase inhibitors: insight into CAII/CAIX specificity from a high-resolution crystal
Pavel Mader1, Adam Pecina2, Petr Cígler2
1Institute 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.
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.
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