SRM-2025: A Theoretically Derived Macrocyclic Polyketide-Nitroimidazole Hybrid with Pan-Filaricidal Activity Across All Life Stages via Dual Wolbachia-Dependent and Nematode-Specific Metabolic Ablation
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We present a de novo conceptual framework for a novel antifilarial compound, SRM-2025 (proposed trade name: FilariCida™) (C32H41N5O7), engineered to achieve high efficacy against all life stages of Onchocerca volvulus and Wuchereria bancrofti, with minimal cytotoxicity to human cells. The design integrates (i) covalent inhibition of Wolbachia ferrochelatase (HemH) and (ii) competitive inhibition of nematode-specific N-myristoyltransferase (NMT). We develop a comprehensive PBPK/PD model with Bayesian uncertainty quantification, global sensitivity analysis (Sobol' indices), and in silico ADMET profiling using established tools like SwissADME. All simulations are reproducible via open Python code using SciPy and NumPy. References are drawn from peer-reviewed journals (2019–2025) and recent WHO reports.