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Reckoning apigenin and kaempferol as a potential multi-targeted inhibitor of EGFR/HER2-MEK pathway of metastatic colorectal cancer identified using rigorous computational workflow

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Abstract

In the past two decades, the treatment of metastatic colorectal cancer (mCRC) has been revolutionized as multiple cytotoxic, biological, and targeted drugs are being approved. Unfortunately, tumors treated with single targeted agents or therapeutics usually develop resistance. According to pathway-oriented screens, mCRC cells evade EGFR inhibition by HER2 amplification and/or activating Kras-MEK downstream signaling. Therefore, treating mCRC patients with dual EGFR/HER2 inhibitors, MEK inhibitors, or the combination of the two drugs envisaged to prevent the resistance development which eventually improves the overall survival rate. In the present study, we aimed to screen potential phytochemical lead compounds that could multi-target EGFR, HER2, and MEK1 (Mitogen-activated protein kinase kinase) using a computer-aided drug design approach that includes molecular docking, endpoint binding free energy calculation using MM-GBSA, ADMET, and molecular dynamics (MD) simulations. Docking studies revealed that, unlike all other ligands, apigenin and kaempferol exhibit the highest docking score against all three targets. Details of ADMET analysis, MM/GBSA, and MD simulations helped us to conclusively determine apigenin and kaempferol as potentially an inhibitor of EGFR, HER2, and MEK1 apigenin and kaempferol against mCRC at a systemic level. Additionally, both apigenin and kaempferol elicited antiangiogenic properties in a dose-dependent manner. Collectively, these findings provide the rationale for drug development aimed at preventing CRC rather than intercepting resistance.

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Abbreviations

CRC:

Colorectal cancer

EGFR:

Epidermal growth factor receptor

HER2:

Human epidermal growth receptor 2

RTK:

Receptor tyrosine kinase

MEK:

Mitogen-activated protein kinase

MM/GBSA:

Molecular mechanics energies/generalized Born and surface area continuum solvation

KMP:

Kaempferol

API:

Apigenin

Lap:

Lapatinib

Tra:

Trametinib

SMILES:

Simplified molecule input line entry specification

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

% HIA:

Human intestinal absorption (%)

CNS permeability:

Central nervous system permeability

GO:

Gene ontology

KEGG:

Kyoto encyclopedia of genes and genomes

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Acknowledgements

The authors acknowledge our host institute, B.V. Patel Pharmaceutical Education Research, and Development (PERD) Centre for providing us with the facilities for our work. We also acknowledge the Department of chemistry, Gujarat University and Computational Chemistry Group (CCG@CUG), Central University of Gujarat, Gandhinagar, for providing computational resources.

Funding

This work was supported by the Department of Science & Technology (DST), Ministry of Science and Technology, Government of India for INSPIRE fellowship (Grant no. IF190211).

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Authors and Affiliations

  1. B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad, Gujarat, India

    Abhilasha Sharma, Sonam Sinha, Jaykant Vora & Neeta Shrivastava

  2. Department of Biochemistry & Forensic Science, University School of Sciences, Gujarat University, Ahmedabad, Gujarat, India

    Abhilasha Sharma & Rakesh M. Rawal

  3. Department of Life Science, University School of Sciences, Gujarat University, Ahmedabad, Gujarat, India

    Abhilasha Sharma, Pooja Rathaur, Jaykant Vora & Rakesh M. Rawal

  4. Kashiv Biosciences, FP 27/2,43, TP-86, BLOCK-B OPP. Apple Woods Township, SP Ring Road, 382210, Ahmedabad, Gujarat, India

    Sonam Sinha

  5. Department of Zoology, Biomedical Technology, and Human Genetics, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India

    Pooja Rathaur & Kaid Johar

  6. School of Applied Material Sciences, Central University of Gujarat, Gandhinagar, India

    Prakash C. Jha

  7. Shri B.V. Patel Education Trust, Ahmedabad, Gujarat, India

    Neeta Shrivastava

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Sharma, A., Sinha, S., Rathaur, P. et al. Reckoning apigenin and kaempferol as a potential multi-targeted inhibitor of EGFR/HER2-MEK pathway of metastatic colorectal cancer identified using rigorous computational workflow. Mol Divers 26, 3337–3356 (2022). https://doi.org/10.1007/s11030-022-10396-7

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