4CAF

Plasmodium vivax N-myristoyltransferase in complex with a benzothiophene inhibitor (compound 34a)

Summary for 4CAF

• Entry DOI: 10.2210/pdb4caf/pdb
• Related: 4CAE
• Descriptor: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, 4-[(2-{5-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1-benzothiophen-3-yl)oxy]piperidine, DIMETHYL SULFOXIDE, ... (9 entities in total)
• Functional Keywords: transferase, myristoylation, malaria, inhibitor, benzothiophene
• Biological source: PLASMODIUM VIVAX (MALARIA PARASITE P. VIVAX)
• Total number of polymer chains: 3
• Total formula weight: 139763.59

Authors

Rackham, M.D.,Brannigan, J.A.,Rangachari, K.,Wilkinson, A.J.,Holder, A.A.,Tate, E.W.,Leatherbarrow, R.J. (deposition date: 2013-10-08, release date: 2014-04-02, Last modification date: 2024-05-08)

Primary citation

Rackham, M.D.,Brannigan, J.A.,Rangachari, K.,Meister, S.,Wilkinson, A.J.,Holder, A.A.,Leatherbarrow, R.J.,Tate, E.W.
Design and Synthesis of High Affinity Inhibitors of Plasmodium Falciparum and Plasmodium Vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (Lelp).
J.Med.Chem., 57:2773-, 2014

PubMed Abstract: N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

PubMed: 24641010
DOI: 10.1021/JM500066B

Experimental method

X-RAY DIFFRACTION (1.7 Å)