Bravizine: A β-Arrestin–Biased Partial Agonist Targeting Dopamine D2 Receptor Hypersensitivity in Tardive Dyskinesia

Background: and Purpose Tardive dyskinesia (TD) emerges from chronic dopamine D2 receptor (D2R) blockade, inducing receptor hypersensitivity and maladaptive signaling. Current therapeutics target downstream symptom modulation without addressing upstream receptor dysregulation. We aimed to design Bravizine, a novel β-arrestin–biased partial agonist, to selectively modulate D2R activity and mitigate hypersensitization. Experimental Approach Bravizine was developed using an AI-augmented ligand optimization workflow (REINVENT 4) incorporating custom scoring functions for receptor bias, docking affinity, and drug-likeness. Molecular docking employed the D2R inactive-state template (6CM4), while molecular dynamics simulations (50 ns) evaluated conformational stability and effector interactions. β-Arrestin engagement was assessed via HDOCK, with hydrogen bond persistence and interaction energy decomposition used to quantify complex stability. Off-target profiles were examined across opioid and serotonergic receptors, and transcriptomic datasets (GSE174407) were analyzed to contextualize D2R expression in antipsychotic-treated samples. Key Results Docking predicted high-affinity D2R binding (−10.8 kcal/mol) with conserved interactions at Asp114 and Phe389, and minimal off-target engagement (> −7.5 kcal/mol). MD simulations revealed stable conformational rearrangements in ICL2 and ICL3, hallmarks of effector bias. Arrestin2 docking yielded a score of −291.9 with ~300 hydrogen bonds maintained, indicating robust β-arrestin engagement. Bias prediction confirmed suppressed G-protein energetics, while in silico pathway analysis suggested partial normalization of D2R-related signaling. Conclusions: and Implications Bravizine exhibits high on-target affinity, favorable physicochemical properties (QED = 0.90, MW = 412 Da, LogP = 3.2), and a strong β-arrestin bias. Computational results support its potential as a first-in-class therapeutic addressing D2R hypersensitization in TD, warranting experimental validation.