In silico mechanism of modified nucleoside antibacterials and a quercetin adjunct: molecular docking, density-functional theory, ADMET and Nrf2/ARE network analysis
Keywords:
modified nucleosides, molecular docking, density-functional theory, ADMET, Nrf2/ARE, quercetinAbstract
Modified nucleoside and nucleotide analogues show antibacterial activity, but the molecular basis of their action and the rationale for a dietary antioxidant adjunct remain unclear. Seven analogues (2FaraA, FluMP, 6ClAraPur, araC, araCMP, cCMP and TTU) and the flavonoid quercetin were profiled by an integrated computational workflow: AutoDockVina docking against three Escherichia coli nucleotide-metabolism enzymes and, for quercetin, against bacterial detoxification enzymes and the mammalian Keap1 Kelch domain; GFN2-xTB and B3LYP density-functional analysis of electronic structure; rule-based ADMET prediction; and KEGG, Gene Ontology and STRING analysis of the Nrf2/ARE module. DNA polymerase III accepted all seven analogues within a narrow affinity window (−5.29 to −6.19 kcal/mol), matching the natural deoxynucleosides and anchored by a conserved GLU775 contact, whereas thymidylate synthase admitted only minimally substituted compounds and ribonucleotide reductase bound none productively. Docking affinity did not correlate with antibacterial potency (PolIII r = −0.16), and frontier-orbital descriptors were near-identical across phosphorylated and free forms; molecular polarity, not reactivity or binding, separated the series, with phosphorylation raising polar surface area beyond the oral-absorption limit. ADMET predicted araC and araCMP as mutagenic and FluMP as the sole Lipinski-noncompliant compound, while quercetin was drug-like and non-hepatotoxic. Quercetin engaged Keap1 at the canonical activator subpocket (−4.82 kcal/mol); enrichment analysis placed the antioxidant gene set in xenobiotic and oxidative-stress responses, and STRING identified NFE2L2 and KEAP1 as principal hubs (combined score 0.999). The data support a target-directed, permeability-limited antibacterial mechanism and a Keap1/Nrf2-mediated cytoprotective role for quercetin.
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