title: QM/MM calculations reveal the different nature of the interaction of two carborane-based sulfamide inhibitors of human carbonic anhydrase II.
abstract: The crystal structures of two novel carborane-sulfamide inhibitors in the complex with human carbonic anhydrase II (hCAII) have been studied using QM/MM calculations. Even though both complexes possess the strongly interacting sulfamide···zinc ion motif, the calculations have revealed the different nature of binding of the carborane parts of the inhibitors. The neutral closo-carborane cage was bound to hCAII mainly via dispersion interactions and formed only very weak dihydrogen bonds. On the contrary, the monoanionic nido cage interacted with the protein mainly via electrostatic interactions. It formed short and strong dihydrogen bonds (stabilization of up to 4.2 kcal/mol; H···H distances of 1.7 Å) with the polar hydrogen of protein NH2 groups. This type of binding is unique among all of the classical organic and inorganic inhibitors of hCAII. Virtual glycine scanning allowed us to identify the amino-acid side chains, which made important contributions to ligand-binding energies. In summary, using QM/MM calculations, we have provided a detailed understanding of the differences between the interactions of two carborane sulfamides, identified the amino acids of hCAII with which they interact, and thus paved the way for the computer-aided rational design of selective boron-cluster-containing hCAII inhibitors.
authors.affiliation: Institute of Organic Chemistry and Biochemistry (IOCB), Academy of Sciences of the Czech Republic , v.v.i., Gilead Sciences and IOCB Research Center, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.
authors.forename: Adam
authors.initials: A
authors.lastname: Pecina
authors.forename: Martin
authors.initials: M
authors.lastname: Lepšík
authors.forename: Jan
authors.initials: J
authors.lastname: Řezáč
authors.forename: Jiří
authors.initials: J
authors.lastname: Brynda
authors.forename: Pavel
authors.initials: P
authors.lastname: Mader
authors.forename: Pavlína
authors.initials: P
authors.lastname: Řezáčová
authors.forename: Pavel
authors.initials: P
authors.lastname: Hobza
authors.forename: Jindřich
authors.initials: J
authors.lastname: Fanfrlík
mesh_terms: D000577:Amides / Q000494:pharmacology*; D001880:Boranes / Q000494:pharmacology*; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D011789:Quantum Theory
chemical_list: D000577:Amides; D001880:Boranes; D002257:Carbonic Anhydrase Inhibitors; D024402:Carbonic Anhydrase II