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Identification of tyrosine kinase inhibitors from Panax bipinnatifidus and Panax pseudoginseng for RTK—HER2 and VEGFR2 receptors, by in silico approach

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Abstract

Breast and stomach cancer is reported as a leading cause for human mortality across the world. The overexpression of receptor tyrosine kinase (RTK) proteins, namely the human epidermal growth factor receptor2 (HER2) and the vascular endothelial growth factor receptor2 (VEGFR2), is reported to be responsible for development and metastasis of breast and stomach cancer. Although several synthetic tyrosine kinase inhibitors (TKIs) as drug candidates targeting RTK—HER2 and VEGFR2 are currently available in the market, these are expensive with the reported side effects. This confers an opportunity for development of alternative novel tyrosine kinase inhibitors (TKIs) for RTK—HER2 and VEGFR2 receptors from the botanical sources. In the present study, we characterized 47 bioactive phytocompounds from the methanol extracts of the rhizomes of Asiatic traditional medicinal herbs—Panax bipinnatifidus and Panax pseudoginseng, of Indian Himalayan landraces using HPLC, GC–MS and high-sensitivity LC–MS tools. We performed molecular docking and molecular dynamics simulation analysis using Schrödinger suite 2020-3 to confirm the TKI phytocompounds showing the best binding affinity towards RTK—HER2 and VEGFR2 receptors. The results of molecular docking studies confirmed that the phytocompound (ligand) luteolin 7-O-glucoside (IHP15) showed the highest binding affinity towards receptor HER2 (PDB ID: 3PP0) with docking score and Glide g score (G-Score) of – 13.272, while chlorogenic acid (IHP12) showed the highest binding affinity towards receptor VEGFR2 (PDB ID: 4AGC) with docking score and Glide g score (G-Score) of – 10.673. Molecular dynamics (MD) simulation analysis carried out for 100 ns has confirmed strong binding interaction between the ligand and receptor complex [luteolin 7-O-glucoside (IHP15) and HER2 (PDB ID: 3PP0)] and is found to be stabilized within 40 to 100 ns of MD simulation, whereas ligand–receptor complex [chlorogenic acid (IPH12) and VEGFR2 (PDB ID: 4AGC)] also showed strong binding interaction and is found to be stabilized within 18–30 ns but slightly deviated during 100 ns of MD simulation. In silico ADME-Tox study using SwissADME revealed that the ligands luteolin 7-O-glucoside (IHP15) and chlorogenic acid (IHP12) have passed majority parameters of the common drug discovery rules. The present study has confirmed luteolin 7-O-glucoside (IHP15) and chlorogenic acid (IHP12) as potential tyrosine kinase inhibitors (TKIs) which were found to inhibit RTKs—HER2 and VEGFR2 receptor proteins, and thus paving the way for development of alternative potential TKIs (drug molecules) for treatment of HER2- and VEGFR2-positive breast and stomach cancer.

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Abbreviations

ADME-Tox :

Adsorption, digestion, metabolism, excretion and toxicity

GC-MS:

Gas chromatography mass spectrometry

HER2:

Human epidermal growth factor receptor2

HPLC:

High-performance liquid chromatography

IHP:

Indian Himalayan Panax

LC-MS:

Liquid chromatography mass spectrometry

MDS:

Molecular dynamics simulation

MERPB:

Methanol extract of rhizome of Panax bipinnatifidus

MERPB:

Methanol extract of rhizome of Panax pseudoginseng

NADPH oxidase:

Nicotinamide adenine dinucleotide phosphate oxidase

NRTK:

Non-receptor tyrosine kinase

PDB ID:

Protein Data Bank identity

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

RTK:

Receptor tyrosine kinase

TK:

Tyrosine kinase

TKI:

Tyrosine kinase inhibitor

VEGFR2:

Vascular endothelial growth factor receptor2

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Acknowledgements

The corresponding author (PKH) is deeply thankful to Department of Biotechnology (DBT), Government of India, for the financial support through DBT Twinning project (Grant No. BT/PR16813/NER/95/300/2015, dated 27 January 2017). The co-corresponding author (HT) expresses thankfulness to Board of Research in Nuclear Science (BRNS), Bhabha Atomic Research Centre (BARC), Trombay, India, under Department of Atomic Energy, Government of India, for funding Support (Grant No. 35/14/16/2016-BRNS/35055, dated 4 June 2016). All the authors are also thankful to Rajiv Gandhi University, Rono Hills, Doimukh, Arunachal Pradesh, India, and National Institute of Technology (NIT), Arunachal Pradesh, India, for laboratory and logistic support. The authors (SM and BT) express thankfulness to National Institute of Electronics and Information Technology, Guwahati, Assam, India, and Guwahati University, Jalukbari, Guwahati, Assam, India, for aiding software-based and computational support to successfully complete these experiments.

Funding

This study was funded by Department of Biotechnology (DBT), Government of India, through DBT Twinning project (Grant No. BT/PR16813/NER/95/300/2015, dated 27 January 2017) and Board of Research in Nuclear Science (BRNS), Bhabha Atomic Research Centre (BARC), Trombay, and Department of Atomic Energy, Government of India (Grant No. 35/14/16/2016-BRNS/35055, dated 4 June 2016).

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Author notes

  1. Dipayan Paul and Saurov Mahanta contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology, National Institute of Technology Arunachal Pradesh, Yupia, Papum Pare, Arunachal Pradesh, 791112, India

    Dipayan Paul, Sanjib Kumar Das, Debmalya Das Gupta & Pallabi Kalita Hui

  2. National Institute of Electronics and Information Technology, Guwahati, Assam, 781008, India

    Saurov Mahanta

  3. Pharmacognosy and Phytochemistry Research Laboratory, Department of Botany, Rajiv Gandhi University, Rono Hills, Doimukh, Arunachal Pradesh, 791112, India

    Hui Tag

  4. Department of Botany, Gauhati University, Guwahati, Assam, 781014, India

    Bhaben Tanti

  5. Food Chemistry Division, ICMR National Institute of Nutrition, Jamai-Osmania PO, Hyderabad, Telangana, 500007, India

    Rajendran Ananthan

  6. Department of Crop Physiology, Assam Agricultural University, Jorhat, Assam, 785013, India

    Ranjan Das

  7. Nuclear Agriculture and Biotechnology Division, Bhabha Atomic Research Centre, Trombay, Mumbai, Maharashtra, 400085, India

    Sanjay Jambhulkar

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  1. Dipayan Paul
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Contributions

HT, PKH, RT, RD, SJ, SM and BT are PIs and research mentors who played a key role in experimental designing, critically verified the data and written this manuscript after several rounds of consultation with all the co-authors involved in the paper. SM, DP, SKD, PKH and BT have significantly contributed in in silico identification of the anti-cancer phytocompounds using molecular docking and molecular dynamics simulation analysis, while HT, PKH, DP, DDG and SKD significantly contributed in phytochemistry data generation and analysis.

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Correspondence to Hui Tag or Pallabi Kalita Hui.

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Paul, D., Mahanta, S., Tag, H. et al. Identification of tyrosine kinase inhibitors from Panax bipinnatifidus and Panax pseudoginseng for RTK—HER2 and VEGFR2 receptors, by in silico approach. Mol Divers 26, 1933–1955 (2022). https://doi.org/10.1007/s11030-021-10304-5

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