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Virtual Screening and Molecular Dynamics Studies of Phytochemicals Targeting Ran GTPase: Identification of Potential
Amka Nagar1, Apurva Prajapati2, Mridula Guin3
1Department of Life Science, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India.
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 (CID_11194, CID_16220, and CID_6220) displayed high stability and were further analyzed by using DFT and ADME/toxicity profiling, among them, CID_11194 and CID_16220 exhibited favorable pharmacokinetic properties, being non-toxic and non-carcinogenic. These findings suggest that the compound CID_16220 may serve as a promising candidate for breast cancer therapy.
Insights
Researchers identified natural compounds that inhibit Ran GTPase, a protein overexpressed in cancers. Compound CID_16220 shows promise as a non-toxic breast cancer therapeutic candidate due to its favorable pharmacokinetic properties.
Area of Science:
- Oncology
- Computational Chemistry
- Pharmacology
Background:
- Ran GTPase is crucial for cell fate and often overexpressed in cancers via PI3K/Akt and ERK/MEK pathways.
- Targeting Ran GTPase is vital for minimizing cancer cell metastasis due to limited specific drugs.
Purpose of the Study:
- To identify novel molecules inhibiting Ran GTPase activity for potential cancer therapy.
- To explore natural compounds as therapeutic agents against Ran GTPase.
Main Methods:
- Virtual screening of the SuperNatural database using the Schrödinger platform.
- Molecular docking, 100 ns molecular dynamics simulations, and DFT-based electronic structure analysis (FMO, MEP).
- ADME/Toxicity profiling to evaluate pharmacokinetic properties and safety.
Main Results:
- Ten natural compounds exhibited strong binding affinity to Ran GTPase (docking scores -13.85 to -10.48 kcal/mol).
- Three compounds (CID_11194, CID_16220, CID_6220) showed high stability in molecular dynamics simulations.
- CID_11194 and CID_16220 demonstrated favorable, non-toxic pharmacokinetic profiles, with CID_16220 identified as a potential breast cancer therapeutic candidate.
Conclusions:
- Virtual screening successfully identified potent natural inhibitors of Ran GTPase.
- Compound CID_16220 exhibits promising therapeutic potential for breast cancer treatment due to its efficacy and safety profile.
- Further investigation into CID_16220 is warranted for its clinical application in oncology.
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