The most prevalent inherited disorder of GABA metabolism, succinic semialdehyde dehydrogenase deficiency (SSADHD) presents a non-specific neurological phenotype associated with physiological accumulation of the major inhibitory neurotransmitter GABA and the GABA- derivative ?-hydroxybutyrate (GHB). An absence of targeted therapy for SSADHD underlies this application?s rationale. Preclinical and clinical studies in SSADHD are underway evaluating the efficacy of antagonizing the receptor interactions of supraphysiological GABA; comparable studies for highly elevated GHB, the biochemical hallmark of the disorder, have been stymied by an absence of structural information for the high-affinity GHB receptor, which severely limits available pharmacological tools. The fact that the GHB receptor antagonist NCS-382 demonstrated preclinical efficacy in a murine model of SSADHD suggests that antagonism of GHB receptors would be clinically desirable. Moreover, ligands with affinity for GHB receptors greater than NCS-382 exist, yet a systematic survey of potential ligands is lacking. Our 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 intoxication, and pharmacological tools to define the molecular identity of the GHB receptor.
Aim 1 is to identify high affinity GHB receptor ligands with ?drug-like? properties employing virtual screening of commercially available, CNS-focused compounds libraries using a validated pharmacophore model, and property- and similarity-based filtering techniques.
Aim 2 is to iteratively refine and validate the pharmacophore model with newly identified ligands of higher binding affinity measured in [3H]NCS-382 displacement assay, and use for further screening to discover compounds with greater affinity. The 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 receptors, and to use this information for the identification of high affinity probe/lead molecules with potential therapeutic application in SSADHD and other forms of GHB intoxication. The 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 SSADHD, and underscores a high degree of potential for translational success.

Public Health Relevance

The most prevalent inherited disorder of GABA metabolism, succinic semialdehyde dehydrogenase deficiency (SSADHD) presents a non-specific neurological phenotype combined with excessive physiological accretion of GABA and the GABA-derivative ?-hydroxybutyric (GHB), and an absence of targeted therapies. While GABA receptors are well characterized, the molecular identity of the high-affinity GHB receptor remains obscure, which limits the pharmacological tools available to antagonize physiologically increased GHB. Here, we propose to apply state-of- the-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 SSADHD, other forms of GHB intoxication, and may assist in elucidating the structure of the high-affinity GHB receptor.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1)
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Morris, Jill A
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Speragen, Inc.
United States
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