Curcuma Longa Phytocompounds: An in Silico Analysis Aimed at Targeting the EGFR Protein as a Potential Anti-cancer Agent

Introduction

Cancer develops in humans as a result of abnormal cell growth secondary to genetic alterations that disrupt normal cellular pathways and functions. Cancer is the second leading cause of mortality worldwide.^[1] The commonly available chemotherapeutic agents for cancer treatment have several drawbacks, including the development of resistance to existing drugs, toxicity of the therapeutic agents, lack of awareness for alternative treatment approaches, and the absence of a specific curative drug. These drawbacks have led researchers to search for novel compounds with anti-lung cancer properties.^[2] Researchers are focusing on natural sources to discover new bioactive compounds.^[3] Traditional medicine practitioners in India, Southeast Asia and China have long recognised the health benefits of Curcuma longa L., or turmeric. Curcumin, the active ingredient in turmeric, was initially used to treat cholecystitis all the way back in 1937.^[3] Curcumins ability to inhibit tumour cell proliferation and migration, as well as inhibit angiogenesis, induce apoptosis, and increase sensitivity to anti-tumour therapy, is mediated by modulation of molecular level targets such as micro-RNAs, transcription factors, genes and cytokines linked to apoptosis and proliferation.^[4,5] Curcumin is widely utilised for the treatment of many different disorders, such as gastrointestinal illness,^[6] liver cirrhosis,^[7] cardiovascular illness,^[8] diabetes,^[9] and cancer, because of its excellent pharmacological action.^[10] Increasing research indicates that curcumin can slow the spread of lung cancer cells by altering their epigenome, preventing cell division, and causing apoptosis.^[11] These findings suggest that curcumin could be very useful in the treatment of cancers, however, our current knowledge of the drug’s functional mechanism prevents us from using it more widely.

Materials and Methods

Results

In this study, we selected curcumin compounds and analysed their ADME properties like gastrointestinal absorption, Lipinski rule and CYP family enzyme inhibitors properties which are shown in Table 1. Apart from this we also checked its toxicity analysis through ProTox-II and its activity is shown in Table 2. Molecular docking analysis shows that curcumin has better interaction with EGFR as compared to the standard drug, the binding energy has been shown in Table 3. Figure 1 shows the KEGG pathway of EGFR in small-cell lung cancer.

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Table 1.

SwissADME web server evaluation of the curcumin’s ADME properties found in Curcuma longa

S.no	Compound	GI absorption	CYP1A2 inhibitor	CYP2C19 inhibitor	CYP2D6 inhibitor	Lipinski	Ghose	Veber	Egan	Muegge	Bioavailability score
1	Curcumin	High	No	No	No	0	0	0	0	0	0.55
2	Paclitaxel	Low	No	No	No	2	3	2	1	3	0.17

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Table 2.

Toxicity profile based on ProTox-II-predicted values of paclitaxel and curcumin; active indicates some toxicity based on predicted data, while inactive indicates no toxicity found

S.no.	Compound	Hepatotoxicity	Carcinogenicity	Immunotoxicity	Mutagenicity	Cytotoxicity
1	Curcumin	Inactive	Inactive	Active	Inactive	Inactive
2	Paclitaxel	Inactive	Inactive	Active	Inactive	Active

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Table 3.

Utilising PyRx to dock the phytocompounds with EGFR and then screen them to identify possible lead molecules based on each one’s unique binding energy profile

S.no.	Compound name	Binding energy (Kcal/mole)	Dissociation constant (µM)	2D interaction	3D interaction	Interacting amino acid
1	Curcumin	–5.64	70.67			ARG 231, GLU 3, ALA 265, CYS 227, ALA 226, LYS 4, GLUT 35, ARG 84
2	Paclitaxel	–3.85	1.38			GLU 3, GLU 233, ARG 231, GLU 35, GLN 59

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The KEGG pathway of EGFR in small cell lung cancer

Discussion

The search for less toxic alternative treatments for lung cancer is the need of the hour. Lung cancer has been shown to exhibit dysregulation of a number of biochemical pathways, which may be targets for therapeutic intervention. These pathways include NF-kB activation, EGFR and PI3/AKT/mTOR signalling, STAT3 expression, the MAP kinase cascade, and VEGF-mediated angiogenesis.^[12,13] While targeted medicines have shown some encouraging results, the limited clinical response observed with single-agent biologic therapy may be partly explained by the intricate interactions among different signalling pathways.^[14] Curcumin is a natural product that is considerably non-toxic and has a variety of inhibitory effects on a number of different pathways involved in carcinogenesis. Curcumin may prove to be an appropriate adjuvant therapy for head and neck cancers that are resistant to currently available treatments due to its broad-reaching mechanism of action and lack of systemic toxicity.^[15] In addition, curcumin has also shown some anti-tumour benefits in the treatment of lung cancers in preclinical studies.^[4] The findings of the current in silico study point towards a favourable ADME and toxicity profile of curcumin in addition to its potential anti-cancer action by targeting the EGFR, a target implicated in several cancers, such as non-small cell lung cancer.

Conclusion

This in silico investigation identified potential for curcumin to target the EGFR protein, a promising strategy for cancer treatment. Curcumin displayed favourable drug-like properties and a potentially safer profile compared to the reference drug paclitaxel. According to the findings of this in silico study, curcumin shares a compatible structure with the EGFR target, which contributes to its high affinity as compared to the standard drug. This was demonstrated by the fact that it had higher free energy and dissociation value. However, in-vitro and in-vivo experiments are crucial to validate these findings and assess curcumin’s efficacy as a potential anti-cancer agent.