1215009-29-2Relevant articles and documents
How to Design Selective Ligands for Highly Conserved Binding Sites: A Case Study Using N-Myristoyltransferases as a Model System
Kersten, Christian,Fleischer, Edmond,Kehrein, Josef,Borek, Christoph,Jaenicke, Elmar,Sotriffer, Christoph,Brenk, Ruth
, p. 2095 - 2113 (2020)
A model system of two related enzymes with conserved binding sites, namely N-myristoyltransferase from two different organisms, was studied to decipher the driving forces that lead to selective inhibition in such cases. Using a combination of computational and experimental tools, two different selectivity-determining features were identified. For some ligands, a change in side-chain flexibility appears to be responsible for selective inhibition. Remarkably, this was observed for residues orienting their side chains away from the ligands. For other ligands, selectivity is caused by interfering with a water molecule that binds more strongly to the off-target than to the target. On the basis of this finding, a virtual screen for selective compounds was conducted, resulting in three hit compounds with the desired selectivity profile. This study delivers a guideline on how to assess selectivity-determining features in proteins with conserved binding sites and to translate this knowledge into the design of selective inhibitors.
Lead optimization of a pyrazole sulfonamide series of trypanosoma brucei N -myristoyltransferase inhibitors: Identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human african trypanosomiasis
Brand, Stephen,Norcross, Neil R.,Thompson, Stephen,Harrison, Justin R.,Smith, Victoria C.,Robinson, David A.,Torrie, Leah S.,McElroy, Stuart P.,Hallyburton, Irene,Norval, Suzanne,Scullion, Paul,Stojanovski, Laste,Simeons, Frederick R. C.,Van Aalten, Daan,Frearson, Julie A.,Brenk, Ruth,Fairlamb, Alan H.,Ferguson, Michael A. J.,Wyatt, Paul G.,Gilbert, Ian H.,Read, Kevin D.
supporting information, p. 9855 - 9869 (2015/02/05)
Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.
N-Myristoyl Transferase Inhibitors
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, (2012/01/13)
The present invention relates to N-heterocyclic sulphonamide compounds, in particular pyrazole sulphonamide compounds, and their use as N-myristoyl transferase inhibitors.
