QM/MM Calculations Reveal the Different Nature of the Interaction of Two Carborane-Based Sulfamide Inhibitors of Human Carbonic Anhydrase II

0424087 - ÚOCHB 2014 RIV US eng J - Článek v odborném periodiku
Pecina, Adam - Lepšík, Martin - Řezáč, Jan - Brynda, Jiří - Mader, Pavel - Řezáčová, Pavlína - Hobza, Pavel - Fanfrlík, Jindřich
QM/MM Calculations Reveal the Different Nature of the Interaction of Two Carborane-Based Sulfamide Inhibitors of Human Carbonic Anhydrase II.
Journal of Physical Chemistry B. Roč. 117, č. 50 (2013), s. 16096-16104. ISSN 1520-6106. E-ISSN 1520-5207
Grant CEP: GA ČR GBP208/12/G016
Grant ostatní: Operational Program Research and Development for Innovations(XE) CZ 1.05/2.1.00/03/0058
Institucionální podpora: RVO:61388963 ; RVO:68378050
Klíčová slova: neutron-capture therapy * dodecaborate cluster lipids * boron clusters
Kód oboru RIV: CF - Fyzikální chemie a teoretická chemie; EB - Genetika a molekulární biologie (UMG-J)
Impakt faktor: 3.377, rok: 2013

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 center dot center dot center dot 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 center dot center dot center dot H distances of 1.7 angstrom) 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.
Trvalý link: http://hdl.handle.net/11104/0230190