NEXUS NIGHTINGALE takes a protein target from sequence to therapeutic dossier — supervised protein folding, mechanism-based routing, molecule design, and a 24-database evidence chain — running on a single desktop computer. No cloud. Every claim citation-referenced.
The production orchestrator (nexus9 dossier) runs intake → supervised fold → mechanism gate → design in one command. Around it sit the rest of the platform: co-evolution, contact prediction, the nine-layer ENNEAD solver, thirteen modality routes, patient and trial matching, the 24-database evidence chain and the TJ Compassion audit.
UniProt, AlphaFold, PDB, PubChem and ClinicalTrials.gov resolve the target at run time — 1,210 aa and 134,277 Da for EGFR.
nexus9 liveA real multiple-sequence alignment from OMA orthologs, storing the co-evolutionary signal the next stage consumes.
nexus9 karen deepmsaTwo independent routes: DCA direct couplings (Morcos 2011) and the ContactNet neural predictor, 95 checkpoints on disk.
nexus9 dca · contactnetNIGHTINGALE predicts the structure and scores it against the experimental reference: TM-score and RMSD, labelled as guided or unguided.
nexus9 foldENNEAD's nine-layer constraint solver folds without a template and refines the result. Research path, not production.
nexus9 ennead foldHierarchical domain decomposition and a binding-pocket finder that recommends a degradation route.
nexus9 fold-domains · pocketGain of function may be degraded; loss of function is protected. The refusal is code — UBE3A and FXN return BLOCKED, not a degrader.
nexus9 therapeuticThirteen routes: AUTOTAC, repurposing, polypharmacology, botanicals, fungi, natural proteins, phage, microbiome, CAR-T, mRNA, psychedelics, gene therapy, peptide.
modality_dbTarget-binding ligand + linker + p62-recruiting ligand. P00533: 446.0 + 194.2 + 257.0 = 897.2 Da, logP 0.9, permeability LOW.
nexus9 ligandAll nine canonical AUTOTAC designs ranked by warhead IC50 — six STRONG, three MODERATE. An estimate, not a docking simulation.
nexus9 dockRule-based structural alerts over the nine designs: hERG, teratogenicity, solubility. Eight score 9/9 risk; predicted, not measured.
nexus9 toxKAREN surfaces twenty-four biomedical databases and eight live connectors into one evidence chain — 101 phenotypes, 36 trials, 77 PGx rules.
nexus9 karen query · pipelineAn eleven-dimensional matcher ranks recruiting trials against the patient's variant, therapy line, biomarkers and safety profile.
nexus9 ptrials forThe TJ Compassion audit and L.O.V.E. gate run before release; the dossier is written to PDF natively, with limitations declared.
nexus9 audit · dossier-pdfFull pipeline architecture — every stage, command and real output →
Each phase has a defined input, a defined method and a defined output. The full architecture — every command, every database and the real output of a run — is on the pipeline page.
Identity first. The sequence, organism, length and mass are fetched from UniProt at run time; a deep ortholog alignment supplies the co-evolutionary signal; DCA and ContactNet produce two independent contact maps. Unknown accessions fail loudly rather than being guessed at.
UniProt accession or gene symbolVerified record · deep MSA · ranked contactsStages 01–03: live · karen deepmsa · dca / contactnet
Structure is solved by the supervised NIGHTINGALE path and, for research, by ENNEAD's nine-layer constraint solver. Both report a TM-score (1.0 perfect, above 0.5 the same fold) and an RMSD in ångströms against the experimental reference. Guided numbers are labelled as reconstruction, not blind prediction; the unguided run is reported separately. Domains and binding pockets are located before any design begins.
Sequence + reference PDBCoordinates · TM-score · RMSD · pocketsStages 04–06: fold · ennead fold/resolve · fold-domains / pocket
The gate reads mechanism before molecule. A gain-of-function target may be degraded; a loss-of-function target is protected, because removing a protein the patient already lacks would make them worse. The refusal is code — UBE3A in Angelman syndrome returns BLOCKED. Thirteen modality routes are available, and the designer computes target-binding ligand, linker and autophagy-recruiting ligand mass, logP and permeability. Two further validation stages run over the nine canonical designs: a docking estimate from warhead IC50 (not a simulation) and a rule-based toxicity screen (structural alerts, not measured).
Target + mechanism classPASSED / BLOCKED · modality · chimera + MWStages 07–11: therapeutic · modality_db · ligand / mass-reduce · dock · tox
Twenty-four biomedical databases are surfaced through KAREN, with live connectors to UniProt, PubChem, PDB, ClinicalTrials.gov, ChEMBL, NCBI Gene, Reactome and OpenTargets. The eleven-dimensional matcher ranks recruiting trials against the patient's variant, therapy line, biomarkers and safety. The TJ Compassion audit and L.O.V.E. gate run before release, and the dossier is rendered to PDF natively — with its limitations declared.
Design + target evidence24-database chain · ranked trials · audited dossierStages 12–14: karen · patient / pgx / ptrials · audit compassion / dossier-pdf
EGFR (UniProt P00533) — the epidermal growth factor receptor, the most-studied oncology kinase — run through the complete pipeline as a demonstration.
| Stage | Result |
|---|---|
| Fold | TM 0.9706 · RMSD 1.64 Å ✓ Supervised fold of P00533 against PDB 1XKK on the corrected 2 Nov 2026 build, reporting the peak TM at 1,000 iterations. The earlier 0.6502 was lowered by a numerically unstable 3×3 superposition in the scorer, not by the folder; it is fixed with a quaternion alignment. The 0.7393 figure came from a stale-checkpoint bug (a 46-residue 1CRN contact map loaded for unrelated targets) and remains retired. Reference-guided reconstruction, not a blind prediction. |
| Eligibility | PASSED ✓ — gain-of-function target, routed degradable. |
| Design | 897 Da chimera — Gefitinib warhead (446 Da) + YTK-105 p62 recruitment ligand (257 Da) + PEG4 linker (194 Da). |
| Report | Citation-referenced dossier — protein biology, structures, drug landscape, resistance map and recommendation. |
Demonstration result. The full dossier for EGFR carries the complete evidence chain — biomarkers, resistance variants, trials and interactions — each citation-referenced.
Each target is routed by its mechanism — a channel disease needs a blocker, a trafficking defect needs a corrector, a toxic gain-of-function may need a degrader. The pipeline applies the right intervention to the right mechanism, and refuses the wrong one.
Browse all fifteen verified dossiers →
Every factual claim — molecular weight, protein identifier, trial status, drug interaction — is checked against a live authoritative source before it is published. This is a design rule of the system, not a marketing promise.
UniProt, RCSB PDB, PubChem and ClinicalTrials.gov are queried live. Every record is verified, not assumed.
A built-in cite-audit flags any citation that does not belong to its claim — rather than letting it ship silently.
When a fact cannot be verified, it is labelled unverified — never presented as certain. Unknown identifiers are rejected, not guessed.
The principle: a recommendation either ships verified, or it does not ship at all. This is the difference between a system that claims accuracy and one that proves it.
Scope: NEXUS NIGHTINGALE produces computational predictions and evidence dossiers for research use. It is not a clinical service, nothing here is medical advice, and no output has regulatory approval. The guided fold figure is a reconstruction baseline — the engine is directed toward the known structure — and the unguided figure is reported alongside it. Every benchmark on this page is reproducible with the shipped build.
A sovereign, self-contained stack — no cloud dependency, no per-query cost, designed to run on commodity hardware.
A supervised folding engine that recovers near-native structure, and reports its own confidence against the reference — sub-ångström agreement on the benchmark target (1M17: TM 0.9801 / RMSD 0.94 Å on the clean build).
Computes designed candidates with explicit molecular weight, linker geometry and property checks — permeability, logP, blood-brain-barrier.
Twenty-four therapeutic databases surfaced into a single evidence chain, with every record carrying its citation.
Runs entirely on local hardware. No data leaves the machine, no external query costs, nothing dependent on a third-party service remaining available.
NEXUS NIGHTINGALE is offered as an in-house analysis service: send a protein target, a UniProt accession or a sequence, and we return a citation-referenced therapeutic dossier. Research use only.
We reply with scope, timeline and data-handling terms before any work begins.