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Published on: May 20, 2015
Discovery of a novel PI3Kα inhibitor for breast cancer therapy via virtual screening method, molecular dynamics
Thitiya Boonma1, Bodee Nutho2, Phongthon Kanjanasirirat3
1Multidisplinary Research Unit of Pure and Applied Chemistry and Supramolecular Chemistry Research Unit, Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahasarakham University, Maha Sarakham, 44150, Thailand.
Abstract:
Phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PI3Kα) is a central signaling enzyme driving cell proliferation and growth in cancers including breast cancer. Selective inhibition of PI3Kα isoform has become a promising therapeutic approach. In this work, 2000 in-house natural compounds were virtually screened against the ATP-binding site of PI3Kα. Of these, 618 compounds were predicted to have acceptable drug-likeness, pharmacokinetic, and toxicity properties based on in silico ADMET screening. Docking analysis highlighted four candidates forming stable hydrogen bonds with key residues V851, S854, and Q859 in the PI3Kα binding pocket. Molecular dynamics simulations were then used to assess their structural features and dynamic stability. Hit 2 was found to form strong hydrogen bonds with E849 and V851 of the PI3Kα protein. MM/GBSA-based binding free energy analysis supported that Hit 2 possessed the most favorable binding affinity to PI3Kα among the identified candidates. In vitro cytotoxicity assays were then performed in MCF-7 and MDA-MB-231 breast cancer cell lines, with alpelisib as a reference compound. Hit 2 reduced cell viability in both cell lines, but its effect was particularly pronounced in MDA-MB-231 cells, a model of triple-negative breast cancer (TNBC). These results suggest that Hit 2 represents a promising natural scaffold for further design and development in breast cancer therapy, with particular relevance for aggressive TNBC.
Insights
Researchers screened natural compounds to find inhibitors for Phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PI3Kα), a key driver of breast cancer. A promising compound, Hit 2, showed significant anti-cancer activity, especially against triple-negative breast cancer.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PI3Kα) is a critical enzyme in cell signaling pathways implicated in cancer proliferation.
- Targeting PI3Kα with selective inhibitors presents a promising therapeutic strategy for various cancers, including breast cancer.
Purpose of the Study:
- To identify novel natural compounds that inhibit PI3Kα activity.
- To evaluate the therapeutic potential of identified compounds against breast cancer cell lines, particularly triple-negative breast cancer (TNBC).
Main Methods:
- Virtual screening of 2000 natural compounds against the PI3Kα ATP-binding site.
- In silico ADMET screening for drug-likeness and pharmacokinetic properties.
- Molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy analysis.
- In vitro cytotoxicity assays using MCF-7 and MDA-MB-231 breast cancer cell lines.
Main Results:
- Four natural compounds were identified as potential PI3Kα inhibitors through docking analysis.
- Hit 2 demonstrated strong binding affinity and stable interactions with key PI3Kα residues.
- Hit 2 exhibited significant cytotoxicity in both MCF-7 and MDA-MB-231 cell lines, with a more pronounced effect on MDA-MB-231 (TNBC) cells.
- The compound's efficacy suggests potential as a therapeutic agent for aggressive breast cancers.
Conclusions:
- Hit 2, a natural compound, shows significant potential as a PI3Kα inhibitor for breast cancer therapy.
- This compound is particularly promising for treating triple-negative breast cancer, an aggressive subtype.
- Further development of Hit 2 as a natural scaffold could lead to novel breast cancer treatments.
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