Three-Dimensional Quantitative Structure-Activity Relationship and Comparative Molecular Field Analysis of Dipeptide Hydroxamic Acid Helicobacter pylori Urease Inhibitors

Abstract

A homology model of Helicobacter pylori urease was developed by using the crystal structure of urease from Klebsiella aerogenes (EC 3.5.1.5) as a template. The acetohydroxamic acid moiety was docked into the active pocket of the enzyme model, followed by relaxation of the complex by use of molecular dynamics. The resulting conformation was used as a template to construct 24 potential dipeptide hydroxamic acid inhibitors with which comparative molecular field analysis (CoMFA) was performed. The resulting model provided a cross-validation correlation coefficient (q 2 L00 ) of 0.610, a conventional r 2 value of 0.988, and an F (Fisher indication of statistical significance) value of 294.88. We were able to validate the CoMFA model by using the 50% inhibitory concentrations of six compounds that were not included in the construction of the model. A very good structural correlation was observed between the amino acids in the model urease's active pocket and the contour maps derived from the CoMFA model. This correlation, accompanied by the validation supplied by use of the CoMFA data, illustrates that the model can aid in the prediction and design of novel H. pylori urease inhibitors.Helicobacter pylori is a gram-negative, spiral bacterium thought to affect about 90% of the world's population (11). It is well accepted that H. pylori infection is etiologically associated with chronic active gastritis, peptic ulcer diseases, mucosa-associated lymphoid tissue-type gastric carcinoma, and other gastric cancers (16). Although H. pylori infection has been implicated as an etiological factor in chronic gastric reflux disease, new studies show that H. pylori infection may provide a protective mechanism against such disease; however, the results of those studies remain controversial (8, 18). Eradication therapy heals gastritis and results in cure of peptic ulcer and the remission of mucosa-associated lymphoid tissue-type gastric carcinomas (22). Although most infections can be controlled by antibiotic therapy (17, 27), H. pylori antibiotic resistance is becoming somewhat commonplace (1). Antibiotic resistance in a microorganism as widespread as H. pylori is a cause for immediate concern and warrants a dedicated search for the discovery of new drug therapies.H. pylori, characterized by its strong urease activity (5), has received a great deal of attention from the scientific community over the past two decades. It is now clear that for survival the organism requires the production of a urease enzyme to help produce ammonia to counteract the strong acidic environment of the stomach (19). It has been estimated that over 5% of the total protein in the cell is represented by this enzyme (12). The urease reaction not only provides an environment with a pH suitable for H. pylori colonization of the stomach mucosal lining but also provides the mechanism for eventual gastric wall damage that increases the overall likelihood and the severity of gastric ulcers (20). Ureases are ubiquitous in nature and are inhibited, in general, by a var...

A review on Hydroxamic Acids: Widespectrum Chemotherapeutic Agents

“…The mode of action of these hydroxamates was established as chelation of iron and inhibition of the enzyme peptide deformylase [60]. Among the glycosyl hydroxamates compound possessing long alkyl chain were found to be most active [61].…”

Improving the Effectivity of Urea Fertilizer in Shallot by Using Urease and Nitrification Inhibitors

“…When urea is hydrolyzed by the urease, most of the ammonium is stored at the site of soil cation exchange, the pH rises briefly, and ammonia gas is produced. Urea inhibitors that are generally used to reduce the transient enzyme activity and slow down the rate at which urea is hydrolyzed (Du et al 2012) are hydroximate (Mishra et al 2002), fluoride (Prakash & Bhusha 1998), thiols (Todd & Hausinger 1989), hydroxyureas (Uesato et al 2004), biscoumarin (Khan et al 2004), and natural extracts (Juszkiewicz et al 2004). The most widely used urease inhibitor is N-(n-Butyl) thiophosphoric triamide (NBTPT or NBPT), which is converted into active N-(n-Butyl) phosphate triamide (NBPTO or BNPO), phenylphosphorodiamidate (PPD/PPDA) and hydroquinone.…”

Reductometric Titration and Quantum Chemical Study of Oxalohydroxamic Acid for Determination of Manganese in Ores and Alloys

“…Extensive works have been carried out on their synthesis [1], complexation with metal ions [2], gravimetry [3], colorimetry [4], kinetics [5][6][7][8][9], spectrophotometry [10] and medical applications [11][12][13][14]. Benzohydroxamic acid was used as a reductometric titrant for determination of manganese, chromium [15] and cerium, uranium [16].…”