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6GNS

Crystal Structure of Leishmania major N-Myristoyltransferase (NMT) With Bound Myristoyl-CoA and an Azepanyl Phenyl Benzylsulphonamide Ligand

Summary for 6GNS
Entry DOI10.2210/pdb6gns/pdb
DescriptorGlycylpeptide N-tetradecanoyltransferase, TETRADECANOYL-COA, methyl 4-(azepan-1-yl)-3-[[4-[4-(1-methylpiperidin-4-yl)butyl]phenyl]sulfonylamino]benzoate, ... (4 entities in total)
Functional Keywordsacyltransferase, transferase, drug discovery
Biological sourceLeishmania major
Total number of polymer chains1
Total formula weight49029.76
Authors
Primary citationHarrison, J.R.,Brand, S.,Smith, V.,Robinson, D.A.,Thompson, S.,Smith, A.,Davies, K.,Mok, N.,Torrie, L.S.,Collie, I.,Hallyburton, I.,Norval, S.,Simeons, F.R.C.,Stojanovski, L.,Frearson, J.A.,Brenk, R.,Wyatt, P.G.,Gilbert, I.H.,Read, K.D.
A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.
J. Med. Chem., 61:8374-8389, 2018
Cited by
PubMed Abstract: Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.
PubMed: 30207721
DOI: 10.1021/acs.jmedchem.8b00884
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.8 Å)
Structure validation

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