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Identification of natural phytochemicals as AKT2 inhibitors using molecular docking and dynamics simulations as
Jibon Kumar Paul1, Mahir Azmal1, Md Naimul Haque Shohan1
1Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh.
Abstract:
The PI3K/AKT/mTOR pathway is central in regulating key cellular processes such as proliferation, survival, metabolism, and angiogenesis. Dysregulation of this pathway, particularly in the AKT2 isoform, is commonly observed in cancers such as breast, ovarian, and pancreatic cancers, leading to enhanced tumor progression, metastasis, and therapeutic resistance. Therefore, targeting AKT2 for inhibition is a promising strategy for cancer therapy. This study utilized molecular docking and dynamics simulations to identify natural phytochemicals that inhibit AKT2. Molecular docking results revealed that millettone (CID 442810) exhibited the highest binding affinity to AKT2, with a docking score of -9.5 kcal/mol, followed by uzarigenin (CID 92760), dihydrobiochanin A (CID 439784), and abyssinone I (CID 442152) with docking scores of -9.0 kcal/mol, -8.9 kcal/mol, and -8.7 kcal/mol respectively, outperforming the control inhibitor, ipatasertib (CID 24788740) docking score of -7.56 kcal/mol. Molecular dynamics simulations indicated that millettone, uzarigenin, and dihydrobiochanin A demonstrated strong binding affinities and stable interactions with AKT2, suggesting their potential as therapeutic agents for cancers that involve AKT2 hyperactivation. Notably, uzarigenin's superior stability, as evidenced by its lower root mean square deviation (RMSD), which measures structural stability, and solvent-accessible surface area (SASA), which indicates molecular compactness, highlights its promise as a potent inhibitor of AKT2. Future in vitro and in vivo studies will be crucial to confirm the efficacy of these inhibitors in reducing tumor progression and their potential applications. Given that AKT2 also plays a role in neuronal survival and plasticity, these compounds may have potential applications in neurodegenerative diseases such as Alzheimer's, warranting further investigation into their dual therapeutic relevance.
Insights
Natural compounds like millettone and uzarigenin show promise for inhibiting AKT2, a key driver in cancer progression and therapeutic resistance. These phytochemicals could offer new avenues for cancer therapy and potentially neurodegenerative diseases.
Area of Science:
- Biochemistry and Molecular Biology
- Computational Chemistry
- Pharmacology
Background:
- The PI3K/AKT/mTOR pathway regulates critical cellular functions including proliferation, survival, metabolism, and angiogenesis.
- Dysregulation of the AKT2 isoform is implicated in various cancers, promoting tumor progression, metastasis, and resistance to therapy.
- Targeting AKT2 presents a significant therapeutic strategy for cancer treatment.
Purpose of the Study:
- To identify natural phytochemicals capable of inhibiting the AKT2 isoform using computational methods.
- To evaluate the binding affinity and stability of identified phytochemicals with AKT2.
- To explore the potential of these compounds as novel therapeutic agents for AKT2-driven cancers and neurodegenerative diseases.
Main Methods:
- Molecular docking simulations were employed to screen a library of natural compounds for AKT2 inhibitory potential.
- Molecular dynamics simulations were conducted to assess the stability and binding interactions of top-ranked inhibitors.
- Binding affinity was quantified using docking scores and validated through simulation-based analyses like RMSD and SASA.
Main Results:
- Millettone demonstrated the highest binding affinity to AKT2 (-9.5 kcal/mol), followed by uzarigenin (-9.0 kcal/mol), dihydrobiochanin A (-8.9 kcal/mol), and abyssinone I (-8.7 kcal/mol).
- These compounds outperformed the control inhibitor ipatasertib (-7.56 kcal/mol).
- Molecular dynamics simulations confirmed stable interactions for millettone, uzarigenin, and dihydrobiochanin A with AKT2, with uzarigenin exhibiting notable stability.
Conclusions:
- Millettone, uzarigenin, and dihydrobiochanin A are potent natural inhibitors of AKT2 identified through computational screening.
- Uzarigenin's superior binding stability suggests it as a particularly promising candidate for further therapeutic development.
- These findings support the potential of these phytochemicals as novel therapeutic agents for AKT2-related cancers and warrant further investigation for neurodegenerative applications.
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