4UWI

Crystal structure of Aspergillus fumigatus N-myristoyl transferase in complex with myristoyl CoA and a pyrazole sulphonamide ligand

4UWI の概要

• エントリーDOI: 10.2210/pdb4uwi/pdb
• 関連するPDBエントリー: 4UWJ
• 分子名称: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, 2,6-dichloro-4-[3-(4-methylpiperazin-1-yl)propyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide, TETRADECANOYL-COA, ... (4 entities in total)
• 機能のキーワード: transferase, drug discovery
• 由来する生物種: ASPERGILLUS FUMIGATUS
• 細胞内の位置: Cytoplasm: Q9UVX3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 48497.15

構造登録者

Robinson, D.A.,Brand, S.,Norcross, N.R.,Thompson, S.,Harrison, J.R.,Smith, V.C.,Torrie, L.S.,McElroy, S.P.,Hallyburton, I.,Norval, S.,Stojanovski, L.,Simeons, F.R.C.,Frearson, J.A.,Brenk, R.,Fairlamb, A.H.,Ferguson, M.A.J.,Wyatt, P.G.,Gilbert, I.H.,Read, K.D. (登録日: 2014-08-12, 公開日: 2014-12-03, 最終更新日: 2024-05-08)

主引用文献

Brand, S.,Norcross, N.R.,Thompson, S.,Harrison, J.R.,Smith, V.C.,Robinson, D.A.,Torrie, L.S.,McElroy, S.P.,Hallyburton, I.,Norval, S.,Scullion, P.,Stojanovski, L.,Simeons, F.R.,van Aalten, D.,Frearson, J.A.,Brenk, R.,Fairlamb, A.H.,Ferguson, M.A.,Wyatt, P.G.,Gilbert, I.H.,Read, K.D.
Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis.
J. Med. Chem., 57:9855-9869, 2014

PubMed Abstract: Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.

PubMed: 25412409
DOI: 10.1021/jm500809c

実験手法

X-RAY DIFFRACTION (1.8 Å)