Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying the SI/II (Switch I/Switch II) groove and locking KRAS in its inactive state. Methods: Phytochemical mining yielded five recurrent phenolics, such as (+)-catechin, hyperin, astragalin, eriodictyol, and the prenylated benzoate amorfrutin A, benchmarked against the covalent inhibitor sotorasib. An in silico cascade combined SI/II docking, multi-parameter ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) filtering, and 100 ns explicit solvent molecular dynamics simulations. Pharmacokinetic modelling predicted oral absorption, Lipinski compliance, mutagenicity, and acute-toxicity class. Results: Hyperin and astragalin showed the strongest non-covalent affinities (−8.6 kcal mol⁻¹) by forging quadridentate hydrogen-bond networks that bridge the P-loop (Asp30/Glu31) to the α3-loop cleft (Asp119/Ala146). Catechin (−8.5 kcal mol⁻¹) balanced polar anchoring with entropic economy. ADME ranked amorfrutin A the highest for predicted oral absorption (93%) but highlighted lipophilic solubility limits; glycosylated flavonols breached Lipinski rules yet remained non-mutagenic with class-5 acute-toxicity liability. Molecular dynamics trajectories confirmed that hyperin clamps the SI/II groove, suppressing loop RMSF below 0.20 nm and maintaining backbone RMSD stability, whereas astragalin retains pocket residence with transient re-orientation. Conclusions: Hyperin emerges as a low-toxicity, mutation-agnostic scaffold that rigidifies inactive KRAS. Deglycosylation, nano-encapsulation, or soft fluorination could reconcile permeability with durable target engagement, advancing Z. lotus phenolics toward broad-spectrum KRAS therapeutics.

Antimicrobial resistance and oxidative-stress-associated disorders motivate the search for edible, multi-component botanical matrices with measurable redox and anti-infective potential. Here, fruits of Ziziphus lotus and Ziziphus jujuba were investigated through an integrated chemistry-to-bioactivity-to-mechanism workflow combining polarity-guided Soxhlet extraction, GC-MS profiling of hexane fractions, UHPLC-MS/MS fingerprinting of acetone/methanolic fractions, total phenolic/flavonoid quantification, DPPH/ABTS antioxidant assays, and antimicrobial benchmarking using inhibition zones and resazurin-based MIC/MBC/MFC assays. The Z. lotus acetone fraction displayed the strongest phenolic enrichment (TPC = 124.33 ± 13.45 mg GAE g^- 1 extract) and the lowest IC₅₀ values (DPPH = 0.77 ± 0.02; ABTS = 0.19 ± 0.02 mg mL^- 1). The lowest antibacterial MICs were observed for the Z. jujuba acetone fraction (0.415 mg mL^- 1 against S. aureus, M. luteus and P. aeruginosa), whereas Rhodotorula glutinis was the most susceptible fungus (MIC/MFC = 0.415/5.20 mg mL^- 1 with Z. jujuba methanol). Because the MIC values remain in the mg mL^- 1 range, the extracts are interpreted as preliminary, moderate-potency anti-infective matrices. Redocking-validated docking, 100 ns molecular dynamics, PCA/free-energy landscape analysis, and 100-snapshot MM/GBSA were used as hypothesis-generating tools and identified stable conformational basins for D3R-4FS3, K3HDH-5JLC and UA-4UYL, with ensemble ΔG_bind estimates of - 45.01, - 38.78 and - 46.06 kcal mol^- 1, respectively. Overall, the work defines polarity-resolved Ziziphus chemotypes, cautiously links them to bioactivity patterns, and prioritizes fractions and compounds for direct enzyme assays, synergy testing, and formulation-oriented validation.