Use of the Novel Site-Directed Enzyme Enhancement Therapy (SEE-Tx) Drug Discovery Platform to Identify Pharmacological Chaperones for Glutaric Acidemia Type 1

Allosteric regulators acting as pharmacological chaperones
hold
promise for innovative therapeutics since they target noncatalytic
sites and stabilize the folded protein without competing with the
natural substrate, resulting in a net gain of function. Exogenous
allosteric regulators are typically more selective than active site
inhibitors and can be more potent than competitive inhibitors when
the natural substrate levels are high. To identify novel structure-targeted
allosteric regulators (STARs) that bind to and stabilize the mitochondrial
enzyme glutaryl-CoA dehydrogenase (GCDH), the computational site-directed
enzyme enhancement therapy (SEE-Tx) technology was applied. SEE-Tx
is an innovative drug discovery platform with the potential to identify
drugs for treating protein misfolding disorders, such as glutaric
acidemia type 1 (GA1) disease. Putative allosteric regulators were
discovered using structure- and ligand-based virtual screening methods
and validated using orthogonal biophysical and biochemical assays.
The computational approach presented here could be used to discover
allosteric regulators of other protein misfolding disorders.