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