2 research outputs found
Controlling the Dissociation of Ligands from the Adenosine A<sub>2A</sub> Receptor through Modulation of Salt Bridge Strength
The
association and dissociation kinetics of ligands binding to
proteins vary considerably, but the mechanisms behind this variability
are poorly understood, limiting their utilization for drug discovery.
This is particularly so for G protein-coupled receptors (GPCRs) where
high resolution structural information is only beginning to emerge.
Engineering the human A<sub>2A</sub> adenosine receptor has allowed
structures to be solved in complex with the reference compound ZM241385
and four related ligands at high resolution. Differences between the
structures are limited, with the most pronounced being the interaction
of each ligand with a salt bridge on the extracellular side of the
receptor. Mutagenesis experiments confirm the role of this salt bridge
in controlling the dissociation kinetics of the ligands from the receptor,
while molecular dynamics simulations demonstrate the ability of ligands
to modulate salt bridge stability. These results shed light on a structural
determinant of ligand dissociation kinetics and identify a means by
which this property may be optimized
Discovery and Structure–Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington’s Disease
Tissue transglutaminase 2 (TG2) is a multifunctional
protein primarily
known for its calcium-dependent enzymatic protein cross-linking activity
via isopeptide bond formation between glutamine and lysine residues.
TG2 overexpression and activity have been found to be associated with
Huntington’s disease (HD); specifically, TG2 is up-regulated
in the brains of HD patients and in animal models of the disease.
Interestingly, genetic deletion of TG2 in two different HD mouse models,
R6/1 and R6/2, results in improved phenotypes including a reduction
in neuronal death and prolonged survival. Starting with phenylacrylamide
screening hit <b>7d</b>, we describe the SAR of this series
leading to potent and selective TG2 inhibitors. The suitability of
the compounds as in vitro tools to elucidate the biology of TG2 was
demonstrated through mode of inhibition studies, characterization
of druglike properties, and inhibition profiles in a
cell lysate assay