Screening oxime libraries by means of mass spectrometry (MS) binding assays: Identification of new highly potent inhibitors to optimized inhibitors γ-aminobutyric acid transporter 1

Felix Kern; Klaus T Wanner

doi:10.1016/j.bmc.2019.02.015

Screening oxime libraries by means of mass spectrometry (MS) binding assays: Identification of new highly potent inhibitors to optimized inhibitors γ-aminobutyric acid transporter 1

Bioorg Med Chem. 2019 Apr 1;27(7):1232-1245. doi: 10.1016/j.bmc.2019.02.015. Epub 2019 Feb 8.

Authors

Felix Kern¹, Klaus T Wanner²

Affiliations

¹ Department Pharmacy - Center for Drug Research, Ludwig-Maximilians-University München, Butenandtstr. 7, 81377 Munich, Germany.
² Department Pharmacy - Center for Drug Research, Ludwig-Maximilians-University München, Butenandtstr. 7, 81377 Munich, Germany. Electronic address: klaus.wanner@cup.uni-muenchen.de.

PMID: 30777661
DOI: 10.1016/j.bmc.2019.02.015

Abstract

Generation and screening of oxime libraries by competitive MS Binding Assays represents a powerful tool for the identification of new compounds, with affinity to mGAT1, the most abundant plasma membrane bound GABA transporter in the CNS. By screening a guvacine derived oxime library, new potent inhibitors of mGAT1 had been revealed. In the present study, oxime libraries generated by reaction of a large excess of a rac-nipecotic acid derivative displaying a hydroxylamine functionality in which various aldehydes under suitable conditions, were examined for new potent inhibitors of mGAT1. The pK_i values obtained of the best hits were compared with those of related compounds displaying a guvacine instead of a nipecotic acid subunit as hydrophilic moiety. Amongst the new compounds one of the most affine ligands of mGAT1 known so far (pK_i = 8.55 ± 0.04) was found.

Keywords: Binding assays; Dynamic combinatorial chemistry; Mass Spectrometry; Membrane proteins; Oximes.

MeSH terms

Binding Sites / drug effects
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HEK293 Cells
Humans
Mass Spectrometry
Molecular Structure
N-Acetylglucosaminyltransferases / antagonists & inhibitors*
N-Acetylglucosaminyltransferases / metabolism
Oximes / chemical synthesis
Oximes / chemistry
Oximes / pharmacology*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Oximes
Small Molecule Libraries
MGAT1 protein, human
N-Acetylglucosaminyltransferases