Molecular modeling of Helicobacter pylori arginase and the inhibitor coordination interactions.

Arginase of the Helicobacter pylori hydrolyzes l-arginine to l-ornithine and urea. H. pylori urease hydrolyzes urea to carbon dioxide and ammonium, which neutralizes acid. Both enzymes are involved in H. pylori nitrogen metabolism. The role of arginase in the physiology of H. pylori is metabolically upstream of urease which contributes in pathogeneses of this bacterium, so arginase could be potential drug target for H. pylori infection. We performed homology modeling of H. pylori arginase using the crystal structure of Bacillus caldovelox arginase as a template, and then refined the model through molecular dynamics (MD) simulations. Different criteria measured by PROCHECK, VERIFY-3D and PROSA were indicative of the proper fold for the predicted structural model of H. pylori arginase. Further evaluation on the model quality was performed by investigating the interaction of some arginase inhibitors with the modeled enzyme. Such interactions were determined employing Autodock 3.0.5 program. Our results are compatible with the published data on contribution of four aspartic acids: D116, D120, D234, D236 and three histidines: H91, H118, H133 for catalysis and stability of binuclear metal center of arginase that have important role in binding and catalytic activity in active site. In the absence of the experimental structure of H. pylori arginase we hope that our model will be useful to provide rational design of novel anti-H. pylori drugs. (c) 2009 Elsevier Inc. All rights reserved.