In Silico Identification of Novel GHB Receptor Ligands for SSADH Deficiency, a Disorder of GABA Metabolism

Summary
The most prevalent inherited disorder of GABA metabolismsuccinic semialdehyde
dehydrogenase deficiencySSADHDpresents a non specific neurological phenotype associated
with physiological accumulation of the major inhibitory neurotransmitter GABA and the GABAderivativehydroxybutyrateGHBAn absence of targeted therapy for SSADHD underlies this
application s rationalePreclinical and clinical studies in SSADHD are underway evaluating the
efficacy of antagonizing the receptor interactions of supraphysiological GABAcomparable
studies for highly elevated GHBthe biochemical hallmark of the disorderhave been stymied by
an absence of structural information for the high affinity GHB receptorwhich severely limits
available pharmacological toolsThe fact that the GHB receptor antagonist NCSdemonstrated preclinical efficacy in a murine model of SSADHD suggests that antagonism of
GHB receptors would be clinically desirableMoreoverligands with affinity for GHB receptors
greater than NCSexistyet a systematic survey of potential ligands is lackingOur hypothesis
is that systematic pharmacophore modeling to identify high potency GHB receptor ligands will
provide novel compounds with potential therapeutic activity for SSADHD and other forms of GHB
intoxicationand pharmacological tools to define the molecular identity of the GHB receptorAimis to identify high affinity GHB receptor ligands withdrug likeproperties employing virtual
screening of commercially availableCNS focused compounds libraries using a validated
pharmacophore modeland propertyand similarity based filtering techniquesAimis to
iteratively refine and validate the pharmacophore model with newly identified ligands of higher
binding affinity measured inH NCSdisplacement assayand use for further screening to
discover compounds with greater affinityThe project s innovation and significance reside in
bringing state of the art in silico methodologies to bear on the production of high resolution
binding site mapping of GHB receptorsand to use this information for the identification of high
affinity probe lead molecules with potential therapeutic application in SSADHD and other forms
of GHB intoxicationThe combined expertise in molecular modeling and decades long preclinical
research in SSADHD blends perfectly with the small business entity with high interest in
developing targeted therapeutics for SSADHDand underscores a high degree of potential for
translational success Project Narrative
The most prevalent inherited disorder of GABA metabolismsuccinic semialdehyde
dehydrogenase deficiencySSADHDpresents a non specific neurological phenotype combined
with excessive physiological accretion of GABA and the GABA derivativehydroxybutyricGHBand an absence of targeted therapiesWhile GABA receptors are well characterizedthe
molecular identity of the high affinity GHB receptor remains obscurewhich limits the
pharmacological tools available to antagonize physiologically increased GHBHerewe propose
to apply state ofthe art in silico methodologies to produce a high resolution binding site map of
GHB receptors in order to identify high affinity probe lead molecules that can provide novel
therapeutics for SSADHDother forms of GHB intoxicationand may assist in elucidating the
structure of the high affinity GHB receptor