5AG7

CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A BENZOMORPHOLINE LIGAND

5AG7 の概要

• エントリーDOI: 10.2210/pdb5ag7/pdb
• 関連するPDBエントリー: 5AG4 5AG5 5AG6 5AGE
• 分子名称: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, ethyl (3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetate, TETRADECANOYL-COA, ... (4 entities in total)
• 機能のキーワード: n-myristoyltransferase, nmt, 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: 51726.38

構造登録者

Robinson, D.A.,Spinks, D.,Smith, V.C.,Thompson, S.,Smith, A.,Torrie, L.S.,McElroy, S.P.,Brand, S.,Brenk, R.,Frearson, J.A.,Read, K.D.,Wyatt, P.G.,Gilbert, I.H. (登録日: 2015-01-29, 公開日: 2015-10-07, 最終更新日: 2024-01-10)

主引用文献

Spinks, D.,Smith, V.,Thompson, S.,Robinson, D.A.,Luksch, T.,Smith, A.,Torrie, L.S.,Mcelroy, S.,Stojanovski, L.,Norval, S.,Collie, I.T.,Hallyburton, I.,Rao, B.,Brand, S.,Brenk, R.,Frearson, J.A.,Read, K.D.,Wyatt, P.G.,Gilbert, I.H.
Development of Small-Molecule Trypanosoma Brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode.
Chemmedchem, 10:1821-, 2015

PubMed Abstract: The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei.

PubMed: 26395087
DOI: 10.1002/CMDC.201500301

実験手法

X-RAY DIFFRACTION (2.6 Å)