6QDC
Leishmania major N-myristoyltransferase in complex with thienopyrimidine inhibitor IMP-0000101
Summary for 6QDC
| Entry DOI | 10.2210/pdb6qdc/pdb |
| Related | 4CGO |
| Descriptor | Glycylpeptide N-tetradecanoyltransferase, TETRADECANOYL-COA, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | transferase, myristoylation, benzothiophene, leishmania |
| Biological source | Leishmania major |
| Total number of polymer chains | 1 |
| Total formula weight | 50290.44 |
| Authors | Brannigan, J.A. (deposition date: 2019-01-01, release date: 2020-05-06, Last modification date: 2024-01-24) |
| Primary citation | 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 Cited by 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: 32575985DOI: 10.1021/acs.jmedchem.0c00570 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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