4UWI
Crystal structure of Aspergillus fumigatus N-myristoyl transferase in complex with myristoyl CoA and a pyrazole sulphonamide ligand
Summary for 4UWI
| Entry DOI | 10.2210/pdb4uwi/pdb |
| Related | 4UWJ |
| Descriptor | 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) |
| Functional Keywords | transferase, drug discovery |
| Biological source | ASPERGILLUS FUMIGATUS |
| Cellular location | Cytoplasm: Q9UVX3 |
| Total number of polymer chains | 1 |
| Total formula weight | 48497.15 |
| Authors | 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. (deposition date: 2014-08-12, release date: 2014-12-03, Last modification date: 2024-05-08) |
| Primary citation | 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 Cited by 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: 25412409DOI: 10.1021/jm500809c PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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