Screening of phytochemicals from Clerodendrum inerme (L.) Gaertn as potential anti-breast cancer compounds targeting EGFR: an in-silico approach

Abstract

Breast cancer (BC) is the most prevalent malignancy among women around the world. The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor (RTK) of the ErbB/HER family. It is essential for triggering the cellular signaling cascades that control cell growth and survival. However, perturbations in EGFR signaling lead to cancer development and progression. Hence, EGFR is regarded as a prominent therapeutic target for breast cancer. Therefore, in the current investigation, EGFR was targeted with phytochemicals from Clerodendrum inerme (L.) Gaertn (C. inerme). A total of 121 phytochemicals identified by gas chromatography-mass spectrometry (GC-MS) analysis were screened against EGFR through molecular docking, ADMET analyses (Absorption, Distribution, Metabolism, Excretion, and Toxicity), PASS predictions, and molecular dynamics simulation, which revealed three potential hit compounds with CIDs 10586 [i.e. alpha-bisabolol (−6.4 kcal/mol)], 550281 [i.e. 2,(4,4-Trimethyl-3-hydroxymethyl-5a-(3-methyl-but-2-enyl)-cyclohexene) (−6.5 kcal/mol)], and 161271 [i.e. salvigenin (−7.4 kcal/mol)]. The FDA-approved drug gefitinib was used to compare the inhibitory effects of the phytochemicals. The top selected compounds exhibited good ADMET properties and obeyed Lipinski’s rule of five (ROF). The molecular docking analysis showed that salvigenin was the best among the three compounds and formed bonds with the key residue Met 793. Furthermore, the molecular mechanics generalized born surface area (MMGBSA) calculations, molecular dynamics simulation, and normal mode analysis validated the binding affinity of the compounds and also revealed the strong stability and compactness of phytochemicals at the docked site. Additionally, DFT and DOS analyses were done to study the reactivity of the compounds and to further validate the selected phytochemicals. These results suggest that the identified phytochemicals possess high inhibitory potential against the target EGFR and can treat breast cancer. However, further in vitro and in vivo investigations are warranted towards the development of these constituents into novel anti-cancer drugs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Clerodendrum inerme
• gas chromatography-mass spectrometry (GC-MS) analysis
• breast cancer
• EGFR (2J6M)
• DFT
• molecular dynamics simulations
• normal mode analysis

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Acknowledgments

The authors would like to thank the Director, Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur for providing the needful facilities. The author also appreciates the Deanship of Scientific Research at Imam Mohammad Ibn Saud University for supporting and supervising this project.

Consent for publication

Yes. All authors have approved the last version of the manuscript for its submission.

Consent to participate

Yes. All authors agreed to participate in this research.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval

Not applicable.

Author contributions

NY and VK conceptualized and designed this study, methodology, and were instrumental in the investigation, analysis, and drafting the entire manuscript with visualizations. AAC, RRKN, SSL, and PKS revised and edited the manuscript in its final form. All authors read and approved the final manuscript.

Data availability statement

All the data generated or analyzed during this study are included in this article.

Additional information

Funding

The authors extend their appreciation to the Deanship of Scientific Research & Innovation, Ministry of Education in Saudi Arabia for funding this research through the project number IFP-IMSUI-2023063.