Article Metrics


Online attention

A molecular hybridization approach for the design of potent, highly selective, and brain-penetrant n-myristoyltransferase inhibitors

DOI: 10.1021/acs.jmedchem.8b00884 DOI Help

Authors: Justin R. Harrison (University of Dundee) , Stephen Brand (University of Dundee) , Victoria Smith (University of Dundee) , David A. Robinson (University of Dundee) , Stephen Thompson (University of Dundee) , Alasdair Smith (University of Dundee) , Kenneth Davies (University of Dundee) , Ngai Mok (University of Dundee) , Leah S. Torrie (University of Dundee) , Iain Collie (University of Dundee) , Irene Hallyburton (University of Dundee) , Suzanne Norval (University of Dundee) , Frederick R. C. Simeons (University of Dundee) , Laste Stojanovski (University of Dundee) , Julie A. Frearson (University of Dundee) , Ruth Brenk (University of Dundee) , Paul G. Wyatt (University of Dundee) , Ian H. Gilbert (University of Dundee) , Kevin D. Read (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2018
Diamond Proposal Number(s): 7705

Open Access Open Access

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.

Diamond Keywords: Sleeping Sickness

Subject Areas: Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Other Facilities: European Synchrotron Radiation Facility (ESRF)

Added On: 24/09/2018 14:05


Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)