3T64

5'-Diphenyl Nucleoside Inhibitors of Plasmodium falciparum dUTPase

3T64 の概要

• エントリーDOI: 10.2210/pdb3t64/pdb
• 分子名称: Deoxyuridine 5'-triphosphate nucleotidohydrolase, putative, 5'-(BENZHYDRYLAMINO)-2',5'-DIDEOXYURIDINE, 2',5'-dideoxy-5'-[(diphenylmethyl)amino]uridine, ... (5 entities in total)
• 機能のキーワード: hydrolase, dutp binding, nucleus, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Plasmodium falciparum 3D7; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 63759.62

構造登録者

Hampton, S.E.,Baragana, B.,Schipani, A.,Bosch-Navarrete, C.,Musso-Buendia, A.,Recio, E.,Kaiser, M.,Whittingham, J.L.,Roberts, S.M.,Shevtsov, M.,Brannigan, J.A.,Kahnberg, P.,Brun, R.,Wilson, K.S.,Gonzalez-Pacanowska, D.,Johansson, N.G.,Gilbert, I.H. (登録日: 2011-07-28, 公開日: 2012-08-29, 最終更新日: 2023-09-13)

主引用文献

Hampton, S.E.,Baragana, B.,Schipani, A.,Bosch-Navarrete, C.,Musso-Buendia, J.A.,Recio, E.,Kaiser, M.,Whittingham, J.L.,Roberts, S.M.,Shevtsov, M.,Brannigan, J.A.,Kahnberg, P.,Brun, R.,Wilson, K.S.,Gonzalez-Pacanowska, D.,Johansson, N.G.,Gilbert, I.H.
Design, synthesis, and evaluation of 5'-diphenyl nucleoside analogues as inhibitors of the Plasmodium falciparum dUTPase.
Chemmedchem, 6:1816-1831, 2011

PubMed Abstract: Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for malaria. We previously reported some 5'-tritylated deoxyuridine analogues (both cyclic and acyclic) as selective inhibitors of the Plasmodium falciparum dUTPase. Modelling studies indicated that it might be possible to replace the trityl group with a diphenyl moiety, as two of the phenyl groups are buried, whereas the third is exposed to solvent. Herein we report the synthesis and evaluation of some diphenyl analogues that have lower lipophilicity and molecular weight than the trityl lead compound. Co-crystal structures show that the diphenyl inhibitors bind in a similar manner to the corresponding trityl derivatives, with the two phenyl moieties occupying the predicted buried phenyl binding sites. The diphenyl compounds prepared show similar or slightly lower inhibition of PfdUTPase, and similar or weaker inhibition of parasite growth than the trityl compounds.

PubMed: 22049550

実験手法

X-RAY DIFFRACTION (1.65 Å)