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Journal of medicinal chemistry
May 09, 2024;67 (9): 7158-7175.

Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design.

Dianne T Keough, Magdalena Petrov��, Gordon King, Michal Kratochv��l, Radek Pohl, Eva Dole��elov��, Alena Z��kov��, Luke W Guddat, Dominik Rejman
Author Information
  1. Dianne T Keough: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
  2. Magdalena Petrov��: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2 , Praha 6 CZ-16610, Czech Republic.
  3. Gordon King: The Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane 4072, Australia.
  4. Michal Kratochv��l: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2 , Praha 6 CZ-16610, Czech Republic. ORCID
  5. Radek Pohl: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2 , Praha 6 CZ-16610, Czech Republic.
  6. Eva Dole��elov��: Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Brani��ovsk�� 31, ��esk�� Bud��jovice CZ-37005, Czech Republic.
  7. Alena Z��kov��: Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Brani��ovsk�� 31, ��esk�� Bud��jovice CZ-37005, Czech Republic. ORCID
  8. Luke W Guddat: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia. ORCID
  9. Dominik Rejman: Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2 , Praha 6 CZ-16610, Czech Republic. ORCID
PMID: 38651522 DOI: 10.1021/acs.jmedchem.4c00021

Abstract

Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by and , , , and . Five compounds synthesized here that contain a purine base covalently linked by a Prolinol group to one or two phosphonate groups have values ranging from 3 nM to >10 ��M, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these Prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against in cell culture, a prodrug exhibited an EC of 10 ��M. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents.

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MeSH Term

Drug Design
Pentosyltransferases
Enzyme Inhibitors
Structure-Activity Relationship
Crystallography, X-Ray
Humans
Models, Molecular
Trypanosoma brucei brucei
Molecular Structure
Catalytic Domain

Chemicals

hypoxanthine-guanine-xanthine phosphoribosyltransferase
Pentosyltransferases
Enzyme Inhibitors
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural
Article has an altmetric score of 2

Word Cloud

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