6QDA

Leishmania major N-myristoyltransferase in complex with quinazoline inhibitor IMP-0000811

6QDA の概要

• エントリーDOI: 10.2210/pdb6qda/pdb
• 関連するPDBエントリー: 4CGO
• 分子名称: Glycylpeptide N-tetradecanoyltransferase, TETRADECANOYL-COA, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: transferase, myristoylation, quinazoline, leishmania
• 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: 50250.34

構造登録者

Brannigan, J.A. (登録日: 2019-01-01, 公開日: 2020-05-06, 最終更新日: 2024-01-24)

主引用文献

Bell, A.S.,Yu, Z.,Hutton, J.A.,Wright, M.H.,Brannigan, J.A.,Paape, D.,Roberts, S.M.,Sutherell, C.L.,Ritzefeld, M.,Wilkinson, A.J.,Smith, D.F.,Leatherbarrow, R.J.,Tate, E.W.
Novel Thienopyrimidine Inhibitors of Leishmania N -Myristoyltransferase with On-Target Activity in Intracellular Amastigotes.
J.Med.Chem., 63:7740-7765, 2020

PubMed Abstract: The leishmaniases, caused by species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. -Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure-activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (), a compound with modest activity against intracellular amastigotes and excellent selectivity (>660-fold) for NMT over human NMTs.

PubMed: 32575985
DOI: 10.1021/acs.jmedchem.0c00570

実験手法

X-RAY DIFFRACTION (1.6 Å)