Dataset Information

A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.

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.

SUBMITTER: Harrison JR

PROVIDER: S-EPMC6167002 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.

Harrison Justin R JR Brand Stephen S Smith Victoria V Robinson David A DA Thompson Stephen S Smith Alasdair A Davies Kenneth K Mok Ngai N Torrie Leah S LS Collie Iain I Hallyburton Irene I Norval Suzanne S Simeons Frederick R C FRC Stojanovski Laste L Frearson Julie A JA Brenk Ruth R Wyatt Paul G PG Gilbert Ian H IH Read Kevin D KD

Journal of medicinal chemistry 20180912 18

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-b ...[more]

PMID: 30207721

Dataset Information

A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.

Publications

A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Similar Datasets

Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors.
| S-EPMC5734605 | biostudies-literature

Structure-based design of potent and selective Leishmania N-myristoyltransferase inhibitors.
| S-EPMC4211304 | biostudies-literature

Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor.
| S-EPMC4434483 | biostudies-literature

Discovery of a Highly Selective, Brain-Penetrant Aminopyrazole LRRK2 Inhibitor.
| S-EPMC4027423 | biostudies-literature

Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors.
| S-EPMC4716601 | biostudies-literature

Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors.
| S-EPMC4027585 | biostudies-literature

Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts.
| S-EPMC10480161 | biostudies-literature

Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit.
| S-EPMC9150124 | biostudies-literature

Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction.
| S-EPMC9340770 | biostudies-literature

Structure-Based Design of Potent and Selective CK1? Inhibitors.
| S-EPMC4025826 | biostudies-other