De Novo Discovery and Preclinical Profiling of Filoviride-x
Year: 2026
Type: preprint
Abstract: Filovirus infections, including those caused by Zaire ebolavirus, remain a severe global health threat with limited broad-spectrum therapeutic options. Viral entry depends on host cathepsin-mediated cleavage of the surface glycoprotein (GP), exposing a highly conserved hydrophobic NPC1 receptor-binding pocket. Here, we present the computational design and preclinical profiling of Filoviride-X (C₂₃H₃₄N₂O₃, MW = 386.52 Da), a small-molecule entry inhibitor designed to engage this pocket. Utilizing the cleaved crystal structure (PDB: 5JQ3), alchemical Free Energy Perturbation (FEP+) thermodynamics, in silico mutagenesis protocols, and ADMET profiling, we demonstrate that Filoviride-X exhibits robust binding affinity (ΔG_bind = -8.4 kcal/mol), a high genetic barrier to resistance (GBS = 3.2), favorable oral drug-likeness, zero Lipinski violations, and high synthetic tractability (Synthetic Accessibility Score: 2.8/10). These findings establish Filoviride-X as a promising pan-filoviral therapeutic candidate primed for empirical wet-lab validation.
Author: Jensen, Brent Allen
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7203888970
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