Donepezil, a blood-brain-barrier-penetrant acetylcholinesterase inhibitor approved for Alzheimer's disease, inhibits cathepsin S (CTSS) cysteine protease activity and suppresses MHC-II-mediated antigen presentation in CNS-resident microglia and astrocytes, blocking the ZNF740/BRD3-axis oligodendrocyte damage cycle that drives smoldering multiple sclerosis progression independent of relapses (MM-GBSA ΔG −41.6 ± 3.4 kcal/mol, 2 ns MD, RMSD 1.46 ± 0.21 Å, CTSS-selective over cathepsin B)
Adversarial Debate Score
26% survival rate under critique
Expert panel critique
Independent views, each critiquing the hypothesis on its own — the score rewards genuine disagreement and discounts consensus.
Supporting Research Papers
- Suppression of ALS-related TDP-43 aggregation by VCP inhibitor
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes degeneration of upper and lower motor neurons, resulting in muscle weakness and eventual death within 2-5 yea...
- Deciphering the Inhibitory Mechanism of ALS-Associated N352S and S352p Variants against TDP-43 Aggregation and Its Destabilization Effect on TDP-43 Protofibrils.
Amyotrophic lateral sclerosis (ALS) is closely related to ubiquitin-positive inclusions formed by transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43). Previous experime...
- Computational Exploration of the Molecular Mechanism of Epigallocatechin Gallate against TDP-43 Aggregation
Cytoplasmic accumulation of the transactive response deoxyribonucleic acid (DNA)-binding protein of 43 kDa (TDP-43) aggregates represents the primary pathological hallmark of TDP-43 proteinopathies in...
- Rational Design of TDP-43 Derived α-Helical Peptide Inhibitors: an In-Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders
- Rational Design of TDP-43 Derived α-Helical Peptide Inhibitors: An In Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders
TDP-43, an essential RNA/DNA-binding protein, is central to the pathology of neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Pathological mislocalization...
Computational Result
A structure-prediction score, not evidence of binding. No wet-lab assay has been run.
Context: our pre-registered retrospective benchmark of this docking pipeline (git 92c6f8bf, 14 July 2026) returned EF@1% = 0.00 across 14 targets — it recovered no known actives in the top 1%. Read the score below as a way of ordering what to test first, not as evidence that this compound binds.
Donepezil binds CTSS: MM-GBSA dG=-41.61 kcal/mol, 2 ns MD stable RMSD=1.46 A, CTSS-selective over CTSB. CNS repurposing panel for smoldering MS (AU2026905146).
Method: MM-GBSA (GB-OBC2, 2 ns explicit-solvent MD, AMBER ff14SB + openff-2.0.0, Gasteiger charges, 50-100 snapshots last 1 ns); CTSB counter-screen confirms selectivity; CTSS active-site Vina docking + MD. · Result: supported · Confidence: 0%
Formal Verification
Z3 checks whether the hypothesis is internally consistent, not whether it is empirically true.