PDBsum entry 6gnh

Transferase

PDB id: 6gnh

Contents

Protein chain

411 a.a.

Ligands

MYA

F4T

Waters ×383

References listed in PDB file

Key reference

• Title: A molecular hybridization approach for the design of potent, Highly selective, And brain-Penetrant n-Myristoyltransferase inhibitors.
• Authors: J.R.Harrison, S.Brand, V.Smith, D.A.Robinson, S.Thompson, A.Smith, K.Davies, N.Mok, L.S.Torrie, I.Collie, I.Hallyburton, S.Norval, F.R.C.Simeons, L.Stojanovski, J.A.Frearson, R.Brenk, P.G.Wyatt, I.H.Gilbert, K.D.Read.
• Ref.: J Med Chem, 2018, 61, 8374-8389. [DOI no: 10.1021/acs.jmedchem.8b00884]
• PubMed id: 30207721

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.