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Target Specific Inhibition of Protein Tyrosine Kinase in Conjunction With Cancer and SARS-COV-2 by Olive
Arabinda Ghosh1, Nobendu Mukerjee2, Bhavdeep Sharma3
1Microbiology Division, Department of Botany, Gauhati University, Guwahati, India.
Abstract:
The fact that viruses cause human cancer dates back to the early 1980s. By reprogramming cellular signaling pathways, viruses encoded protein that can regulate altered control of cell cycle events. Viruses can interact with a superfamily of membrane bound protein, receptor tyrosine kinase to modulate their activity in order to increase virus entrance into cells and promotion of viral replication within the host. Therefore, our study aimed at screening of inhibitors of tyrosine kinase using natural compounds from olive. Protein tyrosine kinase (PTK) is an important factor for cancer progression and can be linked to coronavirus. It is evident that over expression of Protein tyrosine kinase (PTK) enhance viral endocytosis and proliferation and the use of tyrosine kinase inhibitors reduced the period of infection period. Functional network studies were carried out using two major PTKs viz. Anaplastic lymphoma kinase (ALK) and B-lymphocytic kinase (BTK). They are associated with coronavirus in regulation of cell signaling proteins for cellular processes. We virtually screened for 161 library of natural compounds from olive found overexpressed in ALK and BTK in metastatic as well as virus host cells. We have employed both ligand and target-based approach for drug designing by high throughput screening using Multilinear regression model based QSAR and docking. The QSAR based virtual screening of 161 olive nutraceutical compounds has successfully identified certain new hit; Wedelosin, in which, the descriptor rsa (ratio of molecular surface area to the solvent accessible surface area) plays crucial role in deciding Wedelosin's inhibitory potency. The best-docked olive nutraceuticals further investigated for the stability and effectivity of the BTK and ALK during in 150 ns molecular dynamics and simulation. Post simulation analysis and binding energy estimation in MMGBSA further revealed the intensive potential of the olive nutraceuticals in PTK inhibition. This study is therefore expected to widen the use of nutraceuticals from olive in cancer as well as SARS-CoV2 alternative therapy.
Insights
Natural compounds from olive show potential as inhibitors for protein tyrosine kinases (PTKs), which are implicated in both cancer and viral infections like SARS-CoV-2. This research identifies promising therapeutic agents from olive for alternative cancer and viral therapies.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Viruses are known to cause human cancers by reprogramming cellular signaling pathways and interacting with receptor tyrosine kinases.
- Protein tyrosine kinases (PTKs) play a crucial role in cancer progression and are implicated in viral infections, including coronavirus, by enhancing viral entry and replication.
- Overexpression of PTKs like Anaplastic Lymphoma Kinase (ALK) and B-cell Lymphoma 3-pro-B-cell Leukemia/Lymphoma (BTK) is linked to increased viral endocytosis and proliferation.
Purpose of the Study:
- To screen natural compounds from olive for their potential to inhibit PTKs, specifically ALK and BTK.
- To identify novel therapeutic agents from olive for alternative treatments of cancer and SARS-CoV-2 infection.
- To investigate the role of specific molecular descriptors in the inhibitory potency of olive compounds.
Main Methods:
- Virtual screening of 161 olive nutraceutical compounds against ALK and BTK using ligand and target-based approaches.
- High-throughput screening employing Quantitative Structure-Activity Relationship (QSAR) and molecular docking.
- Molecular dynamics simulations and binding energy estimations (MMGBSA) to assess compound stability and effectiveness.
Main Results:
- QSAR-based virtual screening identified Wedelosin as a promising hit, with the molecular descriptor 'rsa' (ratio of molecular surface area to solvent accessible surface area) being critical for its inhibitory potency.
- Molecular dynamics simulations and MMGBSA analysis confirmed the significant potential of selected olive nutraceuticals in inhibiting ALK and BTK.
- The study identified specific olive compounds with strong inhibitory effects on key PTKs involved in viral pathogenesis and cancer.
Conclusions:
- Olive-derived natural compounds, particularly Wedelosin, demonstrate considerable potential as inhibitors of PTKs like ALK and BTK.
- These findings suggest that nutraceuticals from olive could serve as a valuable resource for developing alternative therapies for cancer and SARS-CoV-2.
- Further research into olive compounds could lead to novel therapeutic strategies targeting PTK-mediated diseases.
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