6qd9

Leishmania major N-myristoyltransferase in complex with thienopyrimidine inhibitor IMP-0000065

spinqualitylabelsall models 6qd9, resolution 1.46Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6qd9 is a 1 chain structure with sequence from Leishmania major. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.46Å Ligands: HWT, MG, MYA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q4Q5S8_LEIMA Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity). Publication Abstract from PubMed The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-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 Leishmania 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 Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs. Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes.,Bell AS, Yu Z, Hutton JA, Wright MH, Brannigan JA, Paape D, Roberts SM, Sutherell CL, Ritzefeld M, Wilkinson AJ, Smith DF, Leatherbarrow RJ, Tate EW J Med Chem. 2020 Jul 23;63(14):7740-7765. doi: 10.1021/acs.jmedchem.0c00570. Epub , 2020 Jul 14. PMID:32575985 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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