In Silico-Guided Design of Novel-Scaffold Therapeutics Targeting the Dopamine D3 Receptor

Computational methods in drug discovery reduce research time and costs, and only now can be applied to certain psychiatric conditions due to recent breakthroughs in determining the 3D structures of relevant drug receptors in the brain. A new computational technique, de novo fragment-based drug design (DFDD), was evaluated employing a dopamine D3 receptor (D3R) crystal structure. Three DFDD approaches - scaffold replacement, ligand building, and MedChem Transformations - were assessed in replacing structural portions of eticlopride, a D2/D3R-specific antagonist, to generate compounds of novel drug scaffold. Pharmacological characterization of the compounds determined their binding affinities at target brain receptors. Analogs of scaffold replacement-generated compounds displayed moderate D3R affinity, suggesting that this DFDD method could be an important drug design tool. The findings support the addition of in silico approaches to conventional drug discovery, toward creation of new therapeutics for depression, anxiety, schizophrenia, addiction and other disorders of the central nervous system