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

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• 作者：Adam Pecina ; Martin Lep拧铆k ; Jan 艠ez谩膷 ; Ji艡铆 Brynda ; Pavel Mader ; Pavl铆na 艠ez谩膷ov谩 ; Pavel Hobza ; Jind艡ich Fanfrl铆k
• 刊名：Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：December 19, 2013
• 年：2013
• 卷：117
• 期：50
• 页码：16096-16104
• 全文大小：430K
• 年卷期：v.117,no.50(December 19, 2013)
• ISSN：1520-5207

文摘

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路路路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路路路H distances of 1.7 脜) 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.