4A30

CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A PYRAZOLE SULPHONAMIDE LIGAND

Summary for 4A30

• Entry DOI: 10.2210/pdb4a30/pdb
• Related: 2WSA 4A2Z 4A31 4A32 4A33
• Descriptor: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, CHLORIDE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: acyltransferase, transferase, drug discovery
• Biological source: LEISHMANIA MAJOR
• Total number of polymer chains: 1
• Total formula weight: 52031.81

Authors

Robinson, D.A.,Brand, S.,Fairlamb, A.H.,Ferguson, M.A.J.,Frearson, J.A.,Wyatt, P.G. (deposition date: 2011-09-29, release date: 2011-12-21, Last modification date: 2023-12-20)

Primary citation

Brand, S.,Cleghorn, L.A.,McElroy, S.P.,Robinson, D.A.,Smith, V.C.,Hallyburton, I.,Harrison, J.R.,Norcross, N.R.,Spinks, D.,Bayliss, T.,Norval, S.,Stojanovski, L.,Torrie, L.S.,Frearson, J.A.,Brenk, R.,Fairlamb, A.H.,Ferguson, M.A.,Read, K.D.,Wyatt, P.G.,Gilbert, I.H.
Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.
J. Med. Chem., 55:140-152, 2012

PubMed Abstract: N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

PubMed: 22148754
DOI: 10.1021/jm201091t

Experimental method

X-RAY DIFFRACTION (1.5 Å)