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Interaction of α-Thymidine Inhibitors with Thymidylate Kinase from Plasmodium falciparum.

Authors
  • Chen, Mengshen David1
  • Sinha, Kaustubh1
  • Rule, Gordon S1
  • Ly, Danith H2
  • 1 Department of Biological Sciences , Carnegie Mellon University , 4400 Fifth Avenue , Pittsburgh , Pennsylvania 15213 , United States. , (United States)
  • 2 Department of Chemistry , Carnegie Mellon University , 4400 Fifth Avenue , Pittsburgh , Pennsylvania 15213 , United States. , (United States)
Type
Published Article
Journal
Biochemistry
Publisher
American Chemical Society
Publication Date
May 02, 2018
Identifiers
DOI: 10.1021/acs.biochem.8b00162
PMID: 29684273
Source
Medline
License
Unknown

Abstract

Plasmodium falciparum thymidylate kinase (PfTMK) is a critical enzyme in the de novo biosynthesis pathway of pyrimidine nucleotides. N-(5'-Deoxy-α-thymidin-5'-yl)- N'-[4-(2-chlorobenzyloxy)phenyl]urea was developed as an inhibitor of PfTMK and has been reported as an effective inhibitor of P. falciparum growth with an EC50 of 28 nM [Cui, H., et al. (2012) J. Med. Chem. 55, 10948-10957]. Using this compound as a scaffold, a number of derivatives were developed and, along with the original compound, were characterized in terms of their enzyme inhibition ( Ki) and binding affinity ( KD). Furthermore, the binding site of the synthesized compounds was investigated by a combination of mutagenesis and docking simulations. Although the reported compound is indicated to be highly effective in its inhibition of parasite growth, we observed significantly lower binding affinity and weaker inhibition of PfTMK than expected from the reported EC50. This suggests that significant structural optimization will be required for the use of this scaffold as an effective PfTMK inhibitor and that the inhibition of parasite growth is due to an off-target effect.

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