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Author Notes:

Correspondence: Ichiro Matsumura, Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, Georgia 30322; Tel.: (404) 727-5625; Fax: (404) 727-3452; Email: imatsum@emory.edu

Acknowledgments: We are thankful to Dr. Vern Schramm (Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY) and Dr. Maria Belen Cassera (Department of Biochemistry, Fralin Biotechnology Center, Virginia Polytechnic Institute and State University, Blacksburg, VA) for invaluable suggestions and guidance on the biological studies of adenosine deaminase.

We are also thankful to Dr. Kenneth A. Jacobson and Dr. Stefano Costanzi (Natinal Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD) for reading the manuscript.

Subject:

Research Funding:

AI and IM were supported by a grant from the NIGMS (1 R01 GM086824).

Keywords:

  • computational modeling
  • drug design
  • ligand recognition
  • selective inhibition
  • site-directed mutagenesis
  • adenosine deaminase

The adenosine deaminases of Plasmodium vivax and Plasmodium falciparum exhibit surprising differences in ligand specificity

Tools:

Journal Title:

Journal of Molecular Graphics and Modelling

Volume:

Volume 35

Publisher:

, Pages 43-48

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Plasmodium vivax and P. falciparum cause malaria, so proteins essential for their survival in vivo are potential anti-malarial drug targets. Adenosine deaminases (ADA) catalyze the irreversible conversion of adenosine into inosine, and play a critical role in the purine salvage pathways of Plasmodia and their mammalian hosts. Currently, the number of selective inhibitors of Plasmodium ADAs is limited. One potent and widely used inhibitor of the human ADA (hADA), erythro-9-(2-hydroxy-3-nonly)adenine (EHNA), is a very weak inhibitor (Ki = 120uM) of P. falciparum ADA (pfADA). EHNA-like compounds are thus excluded from consideration as potential inhibitors of Plasmodium ADA in general. However, EHNA activity in P. vivax ADA (pvADA) has not been reported. Here we applied computational molecular modeling to identify the mechanisms of the ligand recognition unique for P. vivax and P. falciparum ADA. Based on the computational studies, we performed molecular biology experiments to show that EHNA is at least 60-fold more potent against pvADA (Ki = 1.9uM) than against pfADA. The D172A pvADA mutant is bound even more tightly (Ki = 0.9uM). These results improve our understanding of the mechanisms of ADA ligand recognition and species-selectivity, and facilitate the rational design of novel EHNA-based ADA inhibitors as anti-malarial drugs. To demonstrate a practical application of our findings we have computationally predicted a novel potential inhibitor of pvADA selective versus the human ADA.

Copyright information:

© 2012 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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