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

Bravizine is a novel β-arrestin–biased partial agonist targeting dopamine D2 receptor (D2R) hypersensitization, a molecular hallmark of tardive dyskinesia (TD). Designed via an AI-augmented ligand optimization workflow using REINVENT 4, Bravizine was optimized for receptor bias prediction, docking affinity, and drug-likeness. Computational studies demonstrate high-affinity D2R binding (−10.8 kcal/mol, 6CM4 template) with conserved interactions at Asp114 and Phe389, minimal predicted off-target binding (>−7.5 kcal/mol for opioid and serotonergic receptors), and stable molecular dynamics over 50,000 ns. Arrestin2 docking (HDOCK) predicts robust β-arrestin complex formation (score −291.9, confidence 0.94), with bias models confirming a β-arrestin–dominant signaling profile and reduced G-protein engagement. Transcriptomic analysis of human frontal cortex datasets (GSE174407) supports the mechanism of D2R desensitization. Bravizine exhibits favorable physicochemical properties (QED=0.90, MW=412 Da, LogP=3.2, TPSA=72 Ų), high predicted on-target affinity, and strong β-arrestin bias. These results, derived entirely from in silico modeling, position Bravizine as a first-in-class candidate for experimental validation in TD therapeutics. The dataset includes: SMILES, SDF files, docking outputs, molecular dynamics simulations, and modeling results. This DOI serves as a permanent, citable record of Bravizine and its computational characterization.