4CAF

Plasmodium vivax N-myristoyltransferase in complex with a benzothiophene inhibitor (compound 34a)

4CAF の概要

• エントリーDOI: 10.2210/pdb4caf/pdb
• 関連するPDBエントリー: 4CAE
• 分子名称: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, 4-[(2-{5-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1-benzothiophen-3-yl)oxy]piperidine, DIMETHYL SULFOXIDE, ... (9 entities in total)
• 機能のキーワード: transferase, myristoylation, malaria, inhibitor, benzothiophene
• 由来する生物種: PLASMODIUM VIVAX (MALARIA PARASITE P. VIVAX)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 139763.59

構造登録者

Rackham, M.D.,Brannigan, J.A.,Rangachari, K.,Wilkinson, A.J.,Holder, A.A.,Tate, E.W.,Leatherbarrow, R.J. (登録日: 2013-10-08, 公開日: 2014-04-02, 最終更新日: 2024-05-08)

主引用文献

Rackham, M.D.,Brannigan, J.A.,Rangachari, K.,Meister, S.,Wilkinson, A.J.,Holder, A.A.,Leatherbarrow, R.J.,Tate, E.W.
Design and Synthesis of High Affinity Inhibitors of Plasmodium Falciparum and Plasmodium Vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (Lelp).
J.Med.Chem., 57:2773-, 2014

PubMed Abstract: N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

PubMed: 24641010
DOI: 10.1021/JM500066B

実験手法

X-RAY DIFFRACTION (1.7 Å)