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Antimicrobial Agents and Chemotherapy, August 2002, p. 2613-2618, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2613-2618.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Hetal Mishra,1 Abby L. Parrill,1,2* and John S. Williamson1,3,4*

Department of Medicinal Chemistry,1 Research Institute of Pharmaceutical Sciences,3 National Center for Natural Products Research, University of Mississippi, University, Mississippi 38677,4 Chemistry Department and Computational Research on Materials Institute, University of Memphis, Memphis, Tennessee 38152-60602

Received 3 July 2001/ Returned for modification 1 March 2002/ Accepted 1 May 2002

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 (q2L00) of 0.610, a conventional r2 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.

* Corresponding authors. Mailing address for John S. Williamson: Department of Medicinal Chemistry, University of Mississippi, University, MS 38677. Phone: (662) 915-7101. Fax: (662) 915-5638. E-mail: mcjsw{at}olemiss.edu. Mailing address for Abby L. Parrill: Chemistry Department and Computational Research on Materials Institute, University of Memphis, Memphis, TN 38152-6060. Phone: (901) 678-2638. Fax: (901) 678-3447. E-mail: aparill{at}memphis.edu.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2613-2618, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2613-2618.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.





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