In Silico study of the active site of Helicobacter pylori urease and its inhibition by hydroxamic acids

Abstract

Hydroxamic acids have emerged as the most promising candidates from among the different classes of inhibitors of urease. In order to understand the mechanism of their action, we have studied in detail using quantum mechanics the active site of Helicobacter pylori urease complexed with acetohydroxamic acid. A diverse library of ligands having the hydroxamate moiety has been prepared and docked into the active site of urease using the QM/MM methodology. It is found that hydroxamic acids with hydrophobic groups attached to them are more potent inhibitors of urease because they can easily penetrate the hydrophobic environment surrounding the active site. The –CONHO− moiety of the hydroxamic acid is also found to be absolutely necessary for chelation and inhibition of urease. In order to determine the roles of residues His 221 and Ala 365, which are not part of the active site, but are nevertheless involved in hydrogen bonding with the ligand, we have performed Molecular Dynamics simulations, both on the wild urease and also on its mutated counterpart, with the two residues substituted, respectively, by alanine and glycine.