6GNU

Crystal Structure of Leishmania major N-Myristoyltransferase (NMT) With Bound Myristoyl-CoA and a Quionlinyl aryl sulphonamide ligand

6GNU の概要

• エントリーDOI: 10.2210/pdb6gnu/pdb
• 分子名称: Glycylpeptide N-tetradecanoyltransferase, TETRADECANOYL-COA, 4-[4-(1-methylpiperidin-4-yl)butyl]-~{N}-[6-(2-methylpropyl)quinolin-5-yl]benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: acyltransferase, transferase, drug discovery
• 由来する生物種: Leishmania major
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 51984.85

構造登録者

Robinson, D.A.,Harrison, J.R.,Brand, S.,Smith, V.C.,Thompson, S.,Smith, A.,Davies, K.,Mok, N.Y.,Torrie, L.S.,Collie, I.,Hallyburton, I.,Norval, S.,Simeons, F.R.C.,Stojanovski, L.,Frearson, J.A.,Brenk, R.,Wyatt, P.G.,Gilbert, I.H.,Read, K.D. (登録日: 2018-05-31, 公開日: 2018-09-26, 最終更新日: 2024-01-17)

主引用文献

Harrison, J.R.,Brand, S.,Smith, V.,Robinson, D.A.,Thompson, S.,Smith, A.,Davies, K.,Mok, N.,Torrie, L.S.,Collie, I.,Hallyburton, I.,Norval, S.,Simeons, F.R.C.,Stojanovski, L.,Frearson, J.A.,Brenk, R.,Wyatt, P.G.,Gilbert, I.H.,Read, K.D.
A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.
J. Med. Chem., 61:8374-8389, 2018

PubMed Abstract: Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.

PubMed: 30207721
DOI: 10.1021/acs.jmedchem.8b00884

実験手法

X-RAY DIFFRACTION (1.54 Å)