Knowledge graph and machine learning-guided virtual screening prioritizes putative blockers of the PSMD11/Rpn6-EBOV glycoprotein interface

Abstract

Host-directed antiviral discovery requires a traceable route from host-factor identification to testable molecular hypotheses. This study developed such a workflow around a host factor associated with Ebola virus glycoprotein (EBOV GP). GFP-GP pulldown coupled with co-immunoprecipitation/mass spectrometry was used to identify GP-associated host candidates. A PSMD11/Rpn6-centred workflow integrated knowledge-graph inference, ligand-only machine learning, ADMETlab profiling and interface-guided docking. Candidate prioritization was assessed through score-weight sensitivity analysis, applicability-domain assessment and docking controls addressing seed reproducibility, search convergence, whole-receptor context and macrocycle ring-conformer sensitivity. Docking scores were contextualized against a matched 59-compound library. The analysis recovered 424 GP-pulldown-specific host proteins and nominated PSMD11/Rpn6 as a proteostasis anchor. The tier-gated knowledge-graph candidate membership was invariant across the tested weight perturbations, with Spearman rho = 0.998 under equal weighting. The selected ExtraTrees model achieved an AUC of 0.912 for the Ki endpoint. Applicability-domain assessment and ADMET profiling differentiated candidate confidence and predicted liabilities. Docking reproducibility checks yielded a maximum standard deviation of 0.05 kcal/mol for conformationally restricted ligands, while macrocyclic candidates showed greater protocol-dependent variability. Rule-based triage integrating upstream evidence, ADMET burden, chemotype diversity and mechanistic coverage returned five candidates: betamethasone, bafilomycin A1, everolimus, pitavastatin and CHEMBL1410015. The workflow links a proteomic host-factor signal to a compact set of chemically diverse hypotheses with explicit evidence sources and limitations. The candidates remain hypotheses for experimental assessment; direct target engagement, interface blockade and antiviral activity are not established by the present study.