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

Bravizine: A β-Arrestin–Biased Partial Agonist Targeting Dopamine D2 Receptor Hypersensitivity in Tardive Dyskinesia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Bravizine: A β-Arrestin–Biased Partial Agonist Targeting Dopamine D2 Receptor Hypersensitivity in Tardive Dyskinesia Aaryan Senthilvanan, Lyudong Yan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8042007/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Tardive dyskinesia (TD) arises from chronic dopamine D2 receptor (D2R) blockade, leading to receptor hypersensitization and maladaptive downstream signaling. To address this, we designed Bravizine, a novel -arrestin–biased partial agonist, using an AI-augmented ligand optimization workflow built on REINVENT 4 with custom scoring functions for receptor bias prediction, docking affinity, and drug-likeness. Molecular docking predicted high-affinity binding of Bravizine to D2R (−10.8 kcal/mol, 6CM4 template), with conserved interactions at Asp114 and Phe389 and minimal predicted off-target affinities at opioid and serotonergic receptors (>−7.5 kcal/mol). Molecular dynamics simulations (50,000 ns) revealed a stable Bravizine–D2R complex characterized by conformational rearrangements in ICL2 and ICL3, structural hallmarks of effector bias. Arrestin2 docking (HDOCK) yielded a score of −291.9 with confidence 0.94 and maintained an average of 300 hydrogen bonds across frames, indicating stable -arrestin complex formation. Bias prediction models further supported a -arrestin–dominant signaling profile, with suppressed G-protein interaction energetics relative to quinpirole control simulations. Transcriptomic analysis of human frontal cortex datasets (GSE174407) indicated elevated DRD2 expression in antipsychotic-treated schizophrenia samples (fold change +1.6, adjusted p<0.05). In silico Bravizine modulation predicted partial normalization of DRD2 -associated pathways, consistent with a receptor desensitization mechanism. Bravizine displays a favorable physicochemical and pharmacological profile (QED=0.90, MW = 412 Da, LogP = 3.2, TPSA = 72 Å​2), high on-target affinity, and robust predicted -arrestin bias. These findings, derived entirely from computational modeling, support Bravizine as a rationally designed, first-in-class therapeutic candidate targeting D2R hypersensitization in tardive dyskinesia and justify future experimental validation. Clinical Pharmacology Dopamine D2 receptor Tardive dyskinesia Biased agonism Beta-arrestin G-protein signaling Transcriptomics Molecular dynamics Antipsychotics Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementalsForBravizine.pdf Supplementary Files - MD Documentation, RMSD Plots, Financial Screenings Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8042007","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":540640949,"identity":"70c4336d-2184-4da6-97b6-0784ea020113","order_by":0,"name":"Aaryan Senthilvanan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYPCCAzx8EIYNEDM2HiCsI+EADxuElQbS0kCUFgaolsMQS/Ep5m9vf/i48McdGTaJ5GcPfu44b7e2/TDQlhqbaFxaJM6cMTaekfCMh00izdyw98zt5G1nEoFajqXlNuDScyOHTZon4TAPG88BMwnettvJZgeAWhgbDuPUIn//+fPfEC3Hv0n+bTuXbHb+IX4tBjcYzJjBWth7zKR52w7Ymd0gYIvhmRxjaZ40sJYyadm25ASzG0BbEvD4Re748YefeWwO2/Mzs2+TfNtmZ292Pv3hgw81Nri9jw4SwSoTiFUOAvakKB4Fo2AUjIKRAQA6XWBkxHbD5wAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0005-7930-2224","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Aaryan","middleName":"","lastName":"Senthilvanan","suffix":""},{"id":540640950,"identity":"cd5d443b-7281-440c-b8a8-16baedc5901c","order_by":1,"name":"Lyudong Yan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lyudong","middleName":"","lastName":"Yan","suffix":""}],"badges":[],"createdAt":"2025-11-05 22:30:14","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8042007/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8042007/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95524356,"identity":"3bc25426-bd49-4d50-958e-e4d13f1d5771","added_by":"auto","created_at":"2025-11-10 10:02:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2336378,"visible":true,"origin":"","legend":"","description":"","filename":"BravizineAArrestinBiasedPartialAgonistTargetingDopamineD2ReceptorHypersensitivityinTardiveDyskinesia10.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8042007/v1_covered_6c4f50fd-3ae5-4327-9b0f-ad4ddeeb89d1.pdf"},{"id":95347966,"identity":"f6eba09a-3ca6-4a1c-8ca9-7a14d5c7cc17","added_by":"auto","created_at":"2025-11-07 03:52:16","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2558869,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Files - MD Documentation, RMSD Plots, Financial Screenings\u003c/p\u003e","description":"","filename":"SupplementalsForBravizine.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8042007/v1/b4741c47e51898399243b9aa.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eBravizine: A β-Arrestin–Biased Partial Agonist Targeting Dopamine D2 Receptor Hypersensitivity in Tardive Dyskinesia\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dopamine D2 receptor, Tardive dyskinesia, Biased agonism, Beta-arrestin, G-protein signaling, Transcriptomics, Molecular dynamics, Antipsychotics","lastPublishedDoi":"10.21203/rs.3.rs-8042007/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8042007/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTardive dyskinesia (TD) arises from chronic dopamine D2 receptor (D2R) blockade, leading to receptor hypersensitization and maladaptive downstream signaling. To address this, we designed Bravizine, a novel -arrestin–biased partial agonist, using an AI-augmented ligand optimization workflow built on REINVENT\u0026nbsp;4 with custom scoring functions for receptor bias prediction, docking affinity, and drug-likeness.\u003c/p\u003e\n\u003cp\u003eMolecular docking predicted high-affinity binding of Bravizine to D2R (−10.8\u0026nbsp;kcal/mol, 6CM4 template), with conserved interactions at Asp114 and Phe389 and minimal predicted off-target affinities at opioid and serotonergic receptors (\u0026gt;−7.5\u0026nbsp;kcal/mol). Molecular dynamics simulations (50,000\u0026nbsp;ns) revealed a stable Bravizine–D2R complex characterized by conformational rearrangements in ICL2 and ICL3, structural hallmarks of effector bias. Arrestin2 docking (HDOCK) yielded a score of −291.9 with confidence 0.94 and maintained an average of 300 hydrogen bonds across frames, indicating stable -arrestin complex formation.\u003c/p\u003e\n\u003cp\u003eBias prediction models further supported a -arrestin–dominant signaling profile, with suppressed G-protein interaction energetics relative to quinpirole control simulations. Transcriptomic analysis of human frontal cortex datasets (GSE174407) indicated elevated \u003cem\u003eDRD2\u003c/em\u003e expression in antipsychotic-treated schizophrenia samples (fold change +1.6, adjusted p\u0026lt;0.05). In silico Bravizine modulation predicted partial normalization of \u003cem\u003eDRD2\u003c/em\u003e-associated pathways, consistent with a receptor desensitization mechanism.\u003c/p\u003e\n\u003cp\u003eBravizine displays a favorable physicochemical and pharmacological profile (QED=0.90, MW = 412\u0026nbsp;Da, LogP = 3.2, TPSA = 72\u0026nbsp;Å​2), high on-target affinity, and robust predicted -arrestin bias. These findings, derived entirely from computational modeling, support Bravizine as a rationally designed, first-in-class therapeutic candidate targeting D2R hypersensitization in tardive dyskinesia and justify future experimental validation.\u003c/p\u003e","manuscriptTitle":"Bravizine: A β-Arrestin–Biased Partial Agonist Targeting Dopamine D2 Receptor Hypersensitivity in Tardive Dyskinesia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-07 03:52:11","doi":"10.21203/rs.3.rs-8042007/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0f519f5a-9a99-43f9-85f3-76bdf487f52c","owner":[],"postedDate":"November 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57586368,"name":"Clinical Pharmacology"}],"tags":[],"updatedAt":"2025-11-07T03:52:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-07 03:52:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8042007","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8042007","identity":"rs-8042007","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}