Structure-based drug design for dopamine D3 receptor

Abstract

D2-like receptors are members of dopamine receptors, including dopamine D2 receptor (D2R), dopamine D3 receptor (D3R), and dopamine D4 receptor (D4R), which modulate behavior, cognition, and emotion. D2-like receptors are critical targets for drug development. Particularly, D3R has been identified as a therapeutic target for antipsychotic and anti-parkinsonian drugs. Recently, the crystal structure of D3R was reported. Here we summarize the available active compounds for D3R and the structure-activity relationships (SAR) studies of them. This provides lead templates for further chemical modification. We describe the structure features of the recent crystal structure of D3R and its difference from other G protein-coupled receptors (GPCRs). We provide the recognition mechanism of the inhibitors of D3R (molecular docking results and molecular dynamics results), which illustrates the interaction between the inhibitors and critical residues of D3R. Finally, we summarize the outlook of drug development for D3R. Our study provides useful information for developing high selective, high potent antagonists and agonists of D3R.