Structure based discovery of dopamine D receptor selective small molecule ligands

Dopamine receptors are a family of G protein coupled receptors GPCRs and can be further divided into D like D and D and D like D D and D subfamilies In this proposal we focus on D receptor which is widely expressed in brain at high levels Modulation of D activity is implicated in the treatment of many psychiatric and neurological disorders such as schizophrenia attention deficit hyperactivity disorder depression Parkinsonandapos s disease and drug addiction One important strategy for the treatment of these diseases is to bring D activity back to a normal level with either agonists or antagonists or allosteric modulators Many D agonists and antagonists have been developed after decades of ligand based efforts However their clinical applications have been greatly limited by their poor pharmacokinetics lack of subtype selectivity and common adverse effects while the optimization based on these compounds are proven to be challenging due to their limited chemical diversity Therefore there is a strong need for novel selective D receptor antagonists agonists or allosteric modulators The goal of this proposal is to solve the crystal structures of D in various activity states and identify chemically novel D selective agonists antagonists and allosteric modulators from virtual screening based on these structures The crystallization part of this proposal will build on the success of solving the structure D Gs protein complex internally by ConfometRx We will aim to improve the resolution of the existing structure and solve more structures of D receptor bound to other agonists dopamine or dopamine like antagonists or the compounds identified from virtual screening Virtual screening efforts of this proposal will aim at identifying chemically novel compounds binding at the orthosteric site and allosteric site s of D based on the structures We will also extend our efforts to its close homolog D receptor based on homology modeling as currently there are no truly selective compounds to distinguish the function of these two subtypes Novel lead compounds will be experimentally validated and subjected to structure based optimization This research will ultimately be commercialized by advancing the most promising compound through clinical trials to create a D specific drug with minimal side effects likely in partnership with a large pharmaceutical company This proposal is in response to the NIMH SBIR PA Novel Tools for Investigating Brain derived GPCRs in Mental Health Research R R Narrative We propose to develop novel drugs targeting the D dopamine receptor by computational screening against the three dimensional structures of the receptor D receptors are found throughout the nervous system and previous research suggests that they play important roles in many psychiatric and neurodegenerative disorders including schizophrenia depression restless leg syndrome and Parkinsonandapos s disease However current drugs do not specifically target D receptor and they possess side effects that limit their use Our proposed approach should lead to novel drugs targeting D receptor that are superior to current available drugs