Virtual Screening and Molecular Dynamics Studies of Phytochemicals Targeting Ran GTPase: Identification of Potential Inhibitors

ABSTRACT Background: Ran GTPase plays a pivotal role in cell fate determination and is frequently overexpressed in various cancers due to dysregulated signaling pathways such as PI3K/Akt and ERK/MEK. Problem statement: There are very limited drugs that specifically target Ran GTPase. Thus, in order to minimize the metastatic potential of cancer cells, it is important to identify molecules that inhibit the activity of Ran GTPase. Methods: To explore novel therapeutic options, we performed a virtual screening of the SuperNatural database targeting Ran GTPase using the Schrödinger platform. Molecular docking was performed using Schrödinger Maestro Academic, and molecular dynamics simulations (100 ns) confirmed the stability of these complexes through sustained hydrogen bonding and other key interactions. Additionally, density functional theory (DFT) ‐based electronic structure analysis, including frontier molecular orbital (FMO) and molecular electrostatic potential (MEP) evaluations, supported their reactivity and binding potential. ADME&T analysis plays a pivotal role in evaluating pharmacokinetic properties. Results: Ten top‐ranking natural compounds were identified with docking scores ranging from –13. 85 to –10. 48 kcal/mol, indicating strong binding affinity at the active site. Virtual screening was further evaluated via molecular docking and intermolecular interaction analysis. Furthermore, molecular dynamics simulations (100 ns) confirmed the stability of these complexes through sustained hydrogen bonding and other key interactions, while three compounds (CID₁1194, CID₁6220, and CID₆220) displayed high stability and were further analyzed by using DFT and ADME/toxicity profiling, among them, CID₁1194 and CID₁6220 exhibited favorable pharmacokinetic properties, being non‐toxic and non‐carcinogenic. These findings suggest that the compound CID₁6220 may serve as a promising candidate for breast cancer therapy.