Exploring PDK3 inhibition in lung cancer through drug repurposing for potential therapeutic interventions
Zeba Firdos Khan1, Aanchal Rathi2, Afreen Khan3
1Department of Biosciences, Faculty of Life Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
Abstract:
The pyruvate dehydrogenase kinase-3 (PDK3) plays an important role in the regulation of a variety of cancers, including lung, by inhibiting the pyruvate dehydrogenase complex (PDC), shifting energy production towards glycolysis necessary for cancer metabolism. In this study, we aimed to identify potential PDK3 inhibitors using a computer-based drug design approach. Virtual screening of the FDA-approved library of 3839 compounds was carried out, from which Bagrosin and Dehydrocholic acid appeared best due to their strong binding affinity, specific interactions, and potential biological characteristics, and thus were selected for further investigations. Both compounds show strong interactions with functionally important residues of the PDK3 with a binding affinity of - 10.6 and - 10.5 kcal/mol for Bagrosin and Dehydrocholic acid, respectively. MD simulation studies for 100 ns suggest the formation of stable complexes, which is evident from RMSD, RMSF, Rg, and SASA parameters. The PCA and FEL analysis suggested admirable global energy minima for the bagrosin-PDK3 and dehydrocholic acid-PDK3 complexes. Finally, we identified FDA-approved drugs, Bagrosin and Dehydrocholic acid, that offer valuable resources and potential therapeutic molecules for targeting lung cancer. Further clinical investigations are required to validate the clinical utility of selected molecules.
Insights
Researchers identified FDA-approved drugs, Bagrosin and Dehydrocholic acid, as potential inhibitors of pyruvate dehydrogenase kinase-3 (PDK3). These compounds show promise for targeting lung cancer by disrupting cancer cell metabolism.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Pyruvate dehydrogenase kinase-3 (PDK3) is crucial in regulating cancer metabolism by inhibiting the pyruvate dehydrogenase complex (PDC).
- This inhibition shifts cellular energy production towards glycolysis, supporting cancer cell proliferation.
Purpose of the Study:
- To identify potential PDK3 inhibitors for lung cancer therapy using computational drug design.
- To evaluate FDA-approved compounds for their ability to bind and inhibit PDK3.
Main Methods:
- Virtual screening of 3839 FDA-approved compounds against PDK3.
- Molecular docking to assess binding affinity and interactions.
- Molecular dynamics (MD) simulations, Principal Component Analysis (PCA), and Free Energy Landscape (FEL) analysis to confirm complex stability and binding modes.
Main Results:
- Bagrosin and Dehydrocholic acid exhibited strong binding affinities (-10.6 and -10.5 kcal/mol, respectively) to PDK3.
- MD simulations confirmed stable complexes between these compounds and PDK3.
- PCA and FEL analyses indicated favorable global energy minima for the drug-PDK3 complexes.
Conclusions:
- Bagrosin and Dehydrocholic acid are identified as promising therapeutic agents targeting PDK3 in lung cancer.
- These FDA-approved drugs represent potential candidates for further clinical investigation in lung cancer treatment.
