A Conceptual and Computational Framework for a Selective Prion-Targeting PROTAC: Illustrating a Reproducible Design and Analysis Pipeline for Isoform-Selective Degradation of PrPSc

Prion diseases, including the transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease, are uniformly fatal neurodegenerative disorders driven by the templated conversion of cellular prion protein (PrPC) into the pathogenic, β-sheet-enriched isoform PrPSc. No disease-modifying therapy currently exists. This paper proposes PrionX-1, a hypothetical bifunctional proteolysis-targeting chimera (PROTAC) that couples an efavirenz-derived warhead (PubChem CID: 64139) to a cereblon (CRBN) E3 ubiquitin ligase recruiter via a polyethylene glycol linker, designed on paper to preferentially engage solvent-exposed β-strand regions (residues 89–140) that distinguish PrPSc from PrPC. The manuscript is deliberately framed as a conceptual and methodological contribution rather than an empirical one: no wet-laboratory synthesis, cell-based assay, animal study, or fully parameterized quantum-chemical calculation on a real structure has been performed. What is genuinely executed, end to end, and reported with its actual numerical output, is a complete open-source analysis pipeline: (i) RDKit-based structural validation of the candidate SMILES string; (ii) numerical integration of an isoform-turnover kinetic model; (iii) a from-scratch Saltelli global sensitivity analysis of that kinetic model (not a placeholder proxy), yielding first- and total-order Sobol indices together with a sample-size robustness check, parameter-interaction indices, and a pooled output-uncertainty characterization; and (iv) a multi-chain Metropolis–Hastings Markov chain Monte Carlo (MCMC) analysis of a synthetic Beta–Binomial efficacy example, cross-validated against the exact conjugate posterior and assessed with Gelman–Rubin R̂ and effective-sample-size diagnostics. Every quantitative result in the text is labeled as either (a) an established literature fact, (b) a genuinely executed and reproducible computation (with source code, software versions, and figures included), or (c) an illustrative or synthetic input value that was not measured for PrionX-1. The density-functional and binding-energy claims present in an earlier draft of this work are explicitly withdrawn, since they were not backed by a completed calculation on a real molecular structure. We close with a falsifiability framework and staged experimental roadmap specifying what would be required to convert this computational framework into empirically supported claims.