2YOG

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

2YOG の概要

• エントリーDOI: 10.2210/pdb2yog/pdb
• 関連するPDBエントリー: 2WWF 2WWG 2WWH 2WWI 2YOF 2YOH
• 分子名称: THYMIDYLATE KINASE, 1-[4-chloranyl-3-(trifluoromethyl)phenyl]-3-[[(2R,3S)-5-[5-methyl-2,4-bis(oxidanylidene)pyrimidin-1-yl]-3-oxidanyl-oxol an-2-yl]methyl]thiourea (3 entities in total)
• 機能のキーワード: transferase, malaria, inhibitor
• 由来する生物種: PLASMODIUM FALCIPARUM
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50407.95

構造登録者

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. (登録日: 2012-10-24, 公開日: 2013-07-24, 最終更新日: 2024-05-08)

主引用文献

Cui, 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

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

実験手法

X-RAY DIFFRACTION (1.5 Å)