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.

Chalcogen and Pnicogen Bonds in Complexes of Neutral Icosahedral and Bicapped Square-Antiprismatic Heteroboranes

“…[30][31][32][33] The properties which make boranes such suitable entities include their hydrophobicity, shape, 3D aromaticity, stability and ability to form dihydrogen bonds. [34][35][36] On that basis, we have recently tackled an inherently electron-deficient heteroborane in order to examine the E-bond effects first. Namely, we synthesized and crystallized the phenyl-substituted thiaborane (12-Ph-closo-1-SB 11 H 10 abbreviated as Ph-SB 11 ) and observed the formation of S...π type Ebonds.…”

The properties of substituted 3D-aromatic neutral carboranes: the potential for σ-hole bonding

“…These include especially their hydrophobicity, 1 low nucleophilicity, 2 Lewis acidity, high symmetry and spherical shape, 3D aromaticity 3 and the ability to form special types of noncovalent interactions, such as dihydrogen 4,5 and s-hole bonding. These include especially their hydrophobicity, 1 low nucleophilicity, 2 Lewis acidity, high symmetry and spherical shape, 3D aromaticity 3 and the ability to form special types of noncovalent interactions, such as dihydrogen 4,5 and s-hole bonding.…”

“…16,17 Structural details about their binding are only known for a few proteins -HIV-1 protease, 18 dihydrofolate reductase 19 (DHFR), carbonic anhydrase 20,21 and vitamin D receptor. 5,23 The interaction repertoire of heteroboranes has, however, been recently expanded by unconventional s-hole bonding, specifically halogen, chalcogen 7 and pnictogen bonding. 5,23 The interaction repertoire of heteroboranes has, however, been recently expanded by unconventional s-hole bonding, specifically halogen, chalcogen 7 and pnictogen bonding.…”

Interface Interactions of the Bowman–Birk Inhibitor BTCI in a Ternary Complex with Trypsin and Chymotrypsin Evaluated by Semiempirical Quantum Mechanical Calculations

“…The “virtual glycine scan” approach was used to identify the energy contributions (ΔΔ G′ int ) of the amino acids at the BTCI‐protease interface toward binding. The glycine mutation was used to avoid new intra and intermolecular interactions and also to minimize the energetic changes due to steric effects.…”