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Structure-based multitargeted docking screening, pharmacokinetics, DFT, and dynamics simulation studies reveal mitoglitazone as a potent inhibitor of cellular survival and stress response proteins of lung cancer

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Abstract

Lung cancer is a disease in which lung cells grow abnormally and uncontrollably, and the cause of it is direct smoking, secondhand smoke, radon, asbestos, and certain chemicals. The worldwide leading cause of death is lung cancer, which is responsible for more than 1.8 million deaths yearly and is expected to rise to 2.2 million by 2030. The most common type of lung cancer is non-small cell lung cancer (NSCLC), which accounts for about 80% and small cell lung cancer (SCLC), which is more aggressive than NSCLC and is often diagnosed later and accounts for 20% of cases. The global concern for lung cancer demands efficient drugs with the slightest chance of developing resistance, and the idea of multitargeted drug designing came up with the solution. In this study, we have performed multitargeted molecular docking studies of Drug Bank compounds with HTVS, SP and XP algorithms followed by MM\GBSA against the four proteins of lung cancer cellular survival and stress responses, which revealed Mitoglitazone as a multitargeted inhibitor with a docking and MM\GBSA score ranging from − 5.784 to − 7.739 kcal/mol and − 25.81 to − 47.65kcal/mol, respectively. Moreover, we performed pharmacokinetics studies and QM-based DFT analysis, showing suitable candidate and interaction pattern analysis revealed the most count of interacting residues was 4GLY, 5PHE, 6ASP, 6GLU, 6LYS, and 6THR. Further, the results were validated with SPC water model-based MD simulation for 100ns in neutralised condition, showing the cumulative deviation and fluctuation < 2Å with many intermolecular interactions. The whole analysis has suggested that Mitoglitazone can be used as a multitargeted inhibitor against lung cancer—however, experimental studies are needed before human use.

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Acknowledgements

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia, for funding this research work through the project number (IF2/PSAU/2022/03/22763).

Funding

The authors are thankful to the Deanship of Scientific Research at Prince Sattam bin Abdulaziz University for funding this work under the General Research Funding program Grant Code Number (IF2/PSAU/2022/03/22763).

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Authors and Affiliations

  1. Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia

    Abdulkarim S. Binshaya, Omar Saad Alkahtani & Ahmed Hjazi

  2. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433, Saudi Arabia

    Fahad M. Aldakheel

  3. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran, 61441, Saudi Arabia

    Hassan H. Almasoudi

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  1. Abdulkarim S. Binshaya
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  5. Hassan H. Almasoudi
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Contributions

ASB: Conceptualisation, Supervision, Data curation, writing—first draft, FMA: Data collection, analysis, reviewing and editing, OSA: Supervision, reviewing and editing, AH: extensive editing of the first draft, HHA: Supervision, visualisation and editing of the first draft.

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Correspondence to Abdulkarim S. Binshaya.

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Binshaya, A.S., Alkahtani, O.S., Aldakheel, F.M. et al. Structure-based multitargeted docking screening, pharmacokinetics, DFT, and dynamics simulation studies reveal mitoglitazone as a potent inhibitor of cellular survival and stress response proteins of lung cancer. Med Oncol 41, 101 (2024). https://doi.org/10.1007/s12032-024-02342-4

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