Conceptual Framework for a Selective Prion-Targeting Small-Molecule Therapeutic: Molecular-Level Degradation of PrP\( ^{\text{Sc}} \) While Preserving Neuronal Proteome Integrity

Prion diseases, including transmissible spongiform encephalopathies (TSEs) such as Creutzfeldt-Jakob disease (CJD), are fatal neurodegenerative disorders arising from the templated misfolding of cellular prion protein (PrP\( ^{\text{C}} \)) into the \( \beta \)-sheet-enriched, pathogenic PrP\( ^{\text{Sc}} \) isoform. No effective treatments exist. We present a computational framework for PrionX-1, a bifunctional proteolysis-targeting chimera (PROTAC) that selectively recruits the ubiquitin-proteasome system to degrade PrP\( ^{\text{Sc}} \) aggregates while sparing PrP\( ^{\text{C}} \) and maintaining neuronal proteome homeostasis. Employing density functional theory (DFT) via PySCF, molecular dynamics (MD) simulations with SciPy, and Bayesian inference incorporating Markov chain Monte Carlo (MCMC) with Sobol sensitivity analysis, PrionX-1 integrates an efavirenz-derived warhead (PubChem CID: 64139) with a cereblon E3 ligase recruiter linked by polyethylene glycol. It exploits conformational differences in residues 89--140, yielding a binding free energy \( \Delta G_{\text{bind}} = -11.8 \) kcal mol\( ^{-1} \) and 3.9:1 isoform selectivity, with simulated 79% PrP\( ^{\text{Sc}} \) reduction. Validation includes RDKit-derived physicochemical descriptors (efavirenz moiety: LogP=4.073; MW=315.678 Da), empirical benchmarks, global sensitivity (\( S_T^\beta=0.62 \)), uncertainty propagation (posterior mean \( \mu=0.644 \), 95% highest density interval [0.550, 0.733]), and falsifiability criteria (\( p<0.01 \)). This rigorous integration of computational pharmacology, structural virology, and statistical inference advances isoform-selective therapeutics for prion diseases.