Identifying protein allosteric transitions for drug discovery using 1D NMR.
 

Identifying protein allosteric transitions for drug discovery using 1D NMR.

Related Articles Identifying protein allosteric transitions for drug discovery using 1D NMR.

ChemMedChem. 2017 Mar 06;:

Authors: Krimm I

Abstract
Allosteric drugs present many advantages over orthosteric drugs and represent therefore an attractive approach in drug discovery, yet highly challenging. First, the binding of ligands in protein allosteric pockets do not ensure allosteric effect and second, allosteric ligands can possess diverse modes of pharmacology even within a compound family. Here we report a new method (1) to detect allosteric communication between protein binding sites and (2) to compare the effect of allosteric ligands on the allosteric transitions of the protein target. The method, illustrated with the Glycogen Phosphorylase protein, consists in comparing 1D NMR STD spectra of a molecule spy (here fragments) in the absence and presence of allosteric ligands. The modification of the STD spectrum of the fragment indicates whether the protein dynamics/conformations have been changed in the presence of the allosteric modulator, therefore highlighting allosteric coupling between the binding pocket of the reference compound (here the fragment) and the allosteric pocket.


PMID: 28263035 [PubMed - as supplied by publisher]



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