QM and QM/MM study on inhibition mechanism of polyphenolic compounds as non-classical inhibitors of α-human carbonic anhydrase (II)

Abstract

Phenolic and polyphenolic compounds are distributed in plant tissues as a secondary metabolite which are compromised in multiple and imperative physiological phenomena. Herein, inhibition mechanism of human carbonic anhydrase isoform II, hCAII, with seven phenolic compounds including phenol, catechol, resorcinol, 4-methyl catechol, vanillic acid, trans-cinnamic acid and ortho-coumaric acid has been investigated using quantum mechanical and ONIOM calculations. B3LYP-D3/6-311++G** method has been employed to calculate the electronic structure and electronic energy of different species through the reaction mechanism path. The model system of hCAVII has been used that includes the core of the catalytic center, Zn 2+ , binds to three histidine residues and a hydroxide ion or water molecule forming a first coordination shell. Thr199 and Glu106 were considered as neighboring residues to the ones binding zinc. All thermodynamic functions through the reaction path are evaluated in different phases. The calculated results indicate that all phenolic inhibitors do not directly interact with the zinc ion in the CA active center, and the presence of aromatic moieties was associated with more effective inhibition. In addition, the implicit and explicit solvent effect has been considered for water solvent using QM and ONIOM (QM/MM) calculations.

QM-cluster model study of CO2 hydration mechanisms in metal-substituted human carbonic anhydrase II

“…Historical differences in opinion arise in part from the advancement of computational resources over time. Initial studies from the 1990s were limited to minimal 18-33 atom quantum mechanical-cluster (QM-cluster) models of only the metal-coordinated atoms and CO 2 [26,35,36], but modeling capabilities have since grown to include simulating the surrounding protein and water environment through both larger QM-cluster models [19,24,37,38] and hybrid quantum mechanical/molecular mechanics (QM/MM) models [27,34,38,39]. Although many QM-only and recent QM/MM models propose the Lindskog path to be the energetically favored mechanism, thermodynamic differences between the two paths are frequently noted to be miniscule and that both paths may be competitive with each other [26,27,[35][36][37]39].…”