In Silico Evaluation of Phytochemical Inhibitors from Artemisia judaica (Sinai Judean Wormwood) Targeting P-Glycoprotein (ABCB1) to Overcome Multidrug Resistance in Cancer

Abstract

Background: Multidrug resistance (MDR) poses a formidable challenge to effective cancer chemotherapy, primarily driven by the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp/ABCB1). P-gp actively pumps a diverse array of chemotherapeutic agents out of cancer cells, reducing intracellular drug accumulation. In this study, we investigated the potential of bioactive phytochemical compounds derived from the Sinai medicinal plant Artemisia judaica (Judean/Sinai Wormwood) as natural inhibitors of human P-glycoprotein (PDB ID: 6C0V). Methods: Using the CB-Dock2 server incorporating AutoDock Vina, structural in silico blind docking simulations were conducted on three active phytochemicals from A. judaica—Reynosin (CID 482788), a Reynosin derivative (CID 146158465), and Reynosin triol (CID 482789)—in comparison with the reference inhibitor Nutlin-3a (CID 98958) and contextualized against classic P-gp modulators (e.g., Verapamil and Tariquidar). In addition, in silico ADMET and pharmacokinetic profiling was conducted using SwissADME to evaluate drug-likeness and safety properties. Results: Our results demonstrated that Nutlin-3a exhibited the strongest binding energy (-8.3 kcal/mol), preferentially targeting the Nucleotide Binding Domain / ATP-binding cavity (Cavity 1, 20,110 ų) and the drug-translocation pocket (Cavity 3, 8,196 ų). Remarkably, the primary A. judaica constituent, Reynosin (CID 482788), displayed a highly comparable binding energy of -8.2 kcal/mol, occupying the central drug-binding channel (Cavity 2, 8,730 ų) through strong hydrophobic interactions, Pi-alkyl contacts, and hydrogen bonding with key residues including PHE335, ILE735, and PHE983. Pharmacokinetic analysis confirmed that Reynosin follows Lipinski's Rule of Five with zero violations. Conclusion: These preliminary in silico findings demonstrate that Artemisia judaica harbors potent natural P-gp inhibitors, particularly Reynosin (CID 482788), offering a promising ethnobotanical lead compound for co-administration in combination therapies to reverse MDR in clinical oncology. Future Molecular Dynamics (MD) simulations (100 ns) are recommended to confirm conformational stability in lipid membrane environments.