The neurotransmitter dopamine (DA) controls many central nervous system functions through three major pathways in the brain, the tuberoinfundibular, the nigrostriatal and the mesocorticolimic (mesocortical and mesolimbic). Each is associated with different processes, and dysfunction can lead to varying diseases and disorders of the central nervous system (CNS). There are five known DA receptors, D2 (D2R) is one of the most abundant DA receptors in the brain, and is thus an important pharmacological target for many CNS diseases. Most of the clinically efficacious antipsychotics used for the treatment of schizophrenia and Parkinson's disease, which are associated with the mesocorticolimbic and nigrostriatal pathways, are D2R agonists or antagonists. However, new drugs with improved efficacy and side-effect profiles are needed for these relatively prevalent diseases. In addition, several drugs abused by humans affect DA neurotransmission in the mesolimbic pathway, due to their effects on reward-related behaviors. Therefore D2R is also a focus for the discovery of pharmacological treatments for substance abuse of a certain class of drugs and addiction disorders for which there are none currently available. The goal of this proposal is to discover novel D2R selective small molecule ligands that can be developed for the treatment of disorders of the CNS. Utilizing a combination of D2R three-dimensional structures, including the active-state structure obtained during our Phase I studies, virtual screening and DNA- encoded library screening, we will identify and develop novel lead compounds. These D2R targeted compounds will be optimized and undergo pre-clinical studies at which point we will seek commercial collaboration with a large pharmaceutical company. This proposal is in response to the Funding Opportunity Announcement PA-18- 574, ?PHS 2018-02 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44] Clinical Trial Not Allowed)?.
We propose to carry out structure-based drug discovery using the three- dimensional structure of the dopamine D2 receptor. Through a combination of virtual screening and the use of DNA-encoded chemical libraries, we will identify small molecules that target the dopamine D2 receptor with high selectivity. This will allow the design and development of novel ligands for improved treatment options for diseases and disorders of the central nervous system.
