Pharmaceutical Discovery

Next steps: a screening project that purpose of which is the discovery of small molecule compounds that can safely and efficiently activate GPR139 in humans. This includes virtual screening, assay development and optimization, compound selection and screening, and active-to-hit work to support hit identification of activators of GPR139. The work plan will allow for the progression of a defined number of compounds into a in vivo pharmaco-kinetics assay and the evaluation of promising candidate compounds in efficacy studies in a alcohol dependent animal model. The screening effort will progress through stages including:

• Structure-based virtual screening – the purpose of this is to employ structure based virtual screening methods to select approximately 500 compounds from a broad diversity set that activate GPR139. 
• Purity analysis and IC50 determination of GPR139 hits in order to perform verification and validation of active compounds, as well as to determine purity of selected active compounds by LC-MS analysis.
• Hit expansion to select 2000 structurally related compounds, which will be screened in primary assay.
• Validation of actives IC50 determination up to 200 compounds
• Determine the purity of all compounds that progressed to potency determination by LC-MS analysis.
• Active hit-to-hit studies – the goal of which is to deliver at least two distinct chemical series families suitable for progression into a hit-to-lead phase
• Hit identification phase resulting in compounds spread over several chemical series libraries that are effective at activating GPR139
• A further screen of these “hit” compounds to select those that have the greatest selectivity for GPR139 verses other coupled proteins receptors

We added the selectivity screen to minimize off target effects in an effort to minimize side effects. We feel this is an important additional step to the current project thatwill significantly further our progress to a viable commercial product.