Tofacitinib (Xeljanz), an FDA-approved JAK1/3 inhibitor, has published case reports demonstrating clinical benefit in Rasmussen's Encephalitis patients. Our computational screen reveals it binds three additional RE-relevant targets beyond its approved JAK mechanism — Granzyme B, CXCR3, and NLRP3 — providing the first mechanistic explanation for its observed efficacy.
Pioglitazone (Actos), an FDA-approved PPARgamma agonist for type 2 diabetes, emerges as the top-ranked candidate in our screen with the highest composite score (86.1/100), strong dual-target binding (GrB + CXCR3), excellent BBB penetration, and a 25-year safety record at ~$0.50/day.
Red nodes = disease targets screened. Green nodes = predicted drug interventions from this study.
Interactive views of the four protein targets used in docking. Drag to rotate. Scroll to zoom. Active site residues highlighted.
Top three candidates from integrated composite scoring (binding affinity + BBB penetration + multi-target coverage + safety profile). All are FDA-approved and prescribable.
Binding free energy (kcal/mol) across all four docking targets. Stronger (more negative) = greener. Tofacitinib and ruxolitinib are the only compounds hitting 3 novel targets.
| Drug | Granzyme B 1IAU |
CXCR3 7VL9 |
NLRP3 7PZC |
P-gp 7A69 |
Novel Targets |
|---|---|---|---|---|---|
| Pioglitazone | -8.3 | -7.2 | -- | -9.4 | 2 |
| Tofacitinib | -7.4 | -6.8 | -5.3 | -9.8 | 3 |
| Ruxolitinib | -7.3 | -7.1 | -5.1 | -- | 3 |
| Minocycline | -8.2 | -6.7 | -7.4 | -10.1 | 3 |
| Deucravacitinib | -8.4 | -- | -- | -- | 1 |
| Ibrutinib | -8.3 | -- | -- | -- | 1 |
| EGCG | -9.3 | -- | -- | -- | 1 |
| Perampanel | -- | -7.6 | -6.8 | -9.4 | 2 |
| Quinidine | -7.6 | -6.5 | -5.9 | -8.5 | 3 |
| Cannabidiol | -6.1 | -6.9 | -6.1 | -8.3 | 3 |
| Baricitinib (neg. control) | -6.0 | -5.4 | -3.9 | -7.2 | 0 |
Ranked by predicted binding free energy to the GrB catalytic site (PDB: 1IAU). Kd estimated from dG = RT ln(Kd). All compounds screened at exhaustiveness=16, seed=42.
| # | Compound | Drug Class | dG (kcal/mol) | Est. Kd (uM) | BBB | Status |
|---|---|---|---|---|---|---|
| 1 | EGCG | Natural polyphenol | -9.3 | 0.15 | 46 | Supplement |
| 2 | Deucravacitinib | TYK2 inhibitor | -8.4 | 0.69 | 61 | FDA 2022 |
| 3 | Pioglitazone | PPARgamma agonist | -8.3 | 0.82 | 88 | FDA 1999 |
| 3 | Ibrutinib | BTK inhibitor | -8.3 | 0.82 | 87 | FDA 2013 |
| 5 | Luteolin | Natural flavonoid | -8.2 | 0.97 | 50 | Supplement |
| 5 | Minocycline | Tetracycline | -8.2 | 0.97 | 37 | FDA |
| 5 | Filgotinib | JAK1 inhibitor | -8.2 | 0.97 | 61 | EMA 2020 |
| 8 | Quercetin | Natural flavonoid | -8.1 | 1.15 | 50 | Supplement |
| 9 | Apigenin | Natural flavonoid | -8.0 | 1.37 | 57 | Supplement |
| 10 | Baicalein | Natural flavonoid | -7.8 | 1.93 | 93 | Supplement |
| 10 | Zanubrutinib | BTK inhibitor | -7.8 | 1.93 | 64 | FDA 2019 |
| 12 | Resveratrol | Natural stilbene | -7.7 | 2.29 | 90 | Supplement |
| 13 | Quinidine | Antiarrhythmic | -7.6 | 2.72 | 100 | FDA |
| 14 | Nafamostat | Protease inhibitor | -7.5 | 3.23 | -- | Japan |
| 15 | Tofacitinib | JAK1/3 inhibitor | -7.4 | 3.83 | 81 | FDA 2012 |
| 15 | Sivelestat | NE inhibitor | -7.4 | 3.83 | -- | Japan |
| 17 | Ruxolitinib | JAK1/2 inhibitor | -7.3 | 4.55 | 89 | FDA 2011 |
| 17 | Berberine | Natural alkaloid | -7.3 | 4.55 | 94 | Supplement |
| 19 | Camostat | Protease inhibitor | -7.1 | 6.42 | -- | Japan |
| 19 | MCC950 | NLRP3 inhibitor | -7.0 | 7.63 | 46 | Research |
Docking software: smina (AutoDock Vina 1.1.2 fork). Targets: Granzyme B (PDB: 1IAU, 2.2A), CXCR3 (PDB: 7VL9, 2.8A), NLRP3 (PDB: 7PZC, 2.8A), P-glycoprotein (PDB: 7A69, 3.5A). Parameters: Exhaustiveness=16, 9 binding modes, seed=42, grid box 25-30A centered on active site. Library: 68 compounds (FDA-approved drugs, natural products, reference antagonists). Ligands prepared with RDKit 2024.03 + OpenBabel 3.1.1, MMFF94 force field minimization. ADMET: 47 compounds profiled for BBB permeability (TPSA, MW, LogP, HBD composite), Lipinski/Veber compliance, PAINS/Brenk filters.
Composite scoring: 0.30 x Binding + 0.25 x BBB + 0.20 x Multi-target + 0.15 x GrB-specific + 0.10 x Safety. All 112 docking runs, log files, and input structures archived and reproducible.