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In-Silico Investigation of Osimertinib Based Compounds as Potential Double Mutant EGFR Kinase Inhibitors Against H1975 Cell Line: Integrating QSAR Modeling, Molecular Docking, MD Simulations, and ADME/Tox Studies

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Abstract

Epidermal growth factor receptor (EGFR) inhibitors have been proven as a high-potential therapeutic target for treating advanced non-small-cell lung cancer (NSCLC). However, many patients still suffer from drug-resistant mutations and drug side effects. The current study aims to investigate Osimertinib-based compounds inhibitory activity against double mutant EGFRL858R/T790M by computational methods of 3D-QSAR, molecular docking, and molecular dynamic (MD) simulations. CoMFA and CoMSIA approaches were used to create the 3D-QSAR models. Molecular docking and molecular dynamics simulation was performed to generate the binding mode and stability of the investigated inhibitors. The CoMFA model achieved good predictability with Q2 = 0.663, R2 = 0.978, SEE = 0.115, and an acceptable value for the coefficient of determination Rtest2 = 0.756. In addition, based on the information retained by the CoMFA contour maps, we proposed four new molecules (T1–T4) with significantly higher inhibitory activity. Furthermore, molecular docking and MD simulation analysis were utilized to confirm the 3D-QSAR results, supporting the stability of the proposed molecules in the 3W2O receptor. Finally, the selected molecules showed favorable pharmacokinetic properties and were non-toxic. The results provide significant information about the proposed Osimertinib-based compounds as potential H1975 Cell Line drugs that encourage further innovative experimental and clinical research.

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Authors and Affiliations

  1. Molecular Chemistry and Natural Substances Laboratory, Department of Chemistry, Faculty of Science, University of Moulay Ismail, Meknes, Morocco

    Salma El Bahi, Meryem Boutalaka, Moulay Ahfid El Alaouy, Yassine Koubi, Khalil El Khatabi, M.’barek Choukrad, Abdelouahid Sbai, Mohammed Bouachrine & Tahar Lakhlifi

  2. National Agricultural Research Center, Al-Baqa, 19381, Jordan

    Marwa Alaqarbeh

  3. EST Khenifra, Sultan Moulay Slimane University, Beni Mellal, Morocco

    Mohammed Bouachrine

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  1. Salma El Bahi
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  2. Meryem Boutalaka
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  3. Marwa Alaqarbeh
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  4. Moulay Ahfid El Alaouy
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  5. Yassine Koubi
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  10. Tahar Lakhlifi
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Contributions

All contributors aided the study's inception and design. El Bahi S, Boutalaka M, El Alaouy M, Koubi Y, and El Khatabi K: presented idea, draft preparation, data handling, data analysis, and writing; Alaqarbeh M: performed the calculations of molecular dynamics, writing, review, and editing; Choukrad M, Sbai A, and Bouachrine M: data analysis, study justification, reviewing, and supervision; Lakhlifi T: reviewing supervision, and project administration.

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Correspondence to Marwa Alaqarbeh or M.’barek Choukrad.

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El Bahi, S., Boutalaka, M., Alaqarbeh, M. et al. In-Silico Investigation of Osimertinib Based Compounds as Potential Double Mutant EGFR Kinase Inhibitors Against H1975 Cell Line: Integrating QSAR Modeling, Molecular Docking, MD Simulations, and ADME/Tox Studies. Chemistry Africa 7, 111–129 (2024). https://doi.org/10.1007/s42250-023-00744-x

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