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2YOF

Plasmodium falciparum thymidylate kinase in complex with a (thio)urea- beta-deoxythymidine inhibitor

Summary for 2YOF
Entry DOI10.2210/pdb2yof/pdb
Related2WWF 2WWG 2WWH 2WWI 2YOG 2YOH
DescriptorTHYMIDYLATE KINASE, 1-[4-chloranyl-3-(trifluoromethyl)phenyl]-3-[[(2R,3S)-5-[5-methyl-2,4-bis(oxidanylidene)pyrimidin-1-yl]-3-oxidanyl-oxolan-2-yl]methyl]thiourea, ACETATE ION, ... (5 entities in total)
Functional Keywordstransferase, malaria
Biological sourcePLASMODIUM FALCIPARUM
Total number of polymer chains3
Total formula weight76233.57
Authors
Huaqing, C.,Carrero-Lerida, J.,Silva, A.P.G.,Whittingham, J.L.,Brannigan, J.A.,Ruiz-Perez, L.M.,Read, K.D.,Wilson, K.S.,Gonzalez-Pacanowska, D.,Gilbert, I.H. (deposition date: 2012-10-24, release date: 2013-07-24, Last modification date: 2023-12-20)
Primary citationCui, H.,Carrero-Lerida, J.,Silva, A.P.G.,Whittingham, J.L.,Brannigan, J.A.,Ruiz-Perez, L.M.,Read, K.D.,Wilson, K.S.,Gonzalez-Pacanowska, D.,Gilbert, I.H.
Synthesis and Evaluation of Alpha-Thymidine Analogues as Novel Antimalarials.
J.Med.Chem., 55:10948-, 2012
Cited by
PubMed Abstract: Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-α- and β-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-α-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 μM).
PubMed: 23240776
DOI: 10.1021/JM301328H
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.82 Å)
Structure validation

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