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Published online on: 25-06-2019
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801D. Anusha*
, S. Sharanya, Ramya and Darling Chellathai David
Department of Pharmacology, SRIHER, Chennai, India.
Corresponding Author E-mail: drdanusha@gmail.com
DOI : https://dx.doi.org/10.13005/bpj/1727
Abstract
The lymphomas are a heterogeneous group of cancer of the lymphocytes and the lymphatic system and accounts for up to 3% of all malignancies.1 Most of the drugs currently used for the treatment of lymphoma produce various side effects, hence in this study, we focus on natural compounds, obtained from the medicinal plant Vitex negundo, which exhibits selective toxicity against cancer cells. The objective of this research was to formulate the binding energies and interaction of selected phytochemicals present in the medicinal plant Vitex negundo2 against anaplastic lymphoma kinase protein, which is overexpressed in an anaplastic large cell lymphoma.3, 4,5 The structure of mutant human anaplastic lymphoma kinase protein was retrieved from the Protein Data Bank (PDB ID:4ANL ) and the 3D chemical structure of the phytochemicals present in the medicinal plant Vitex negundo was obtained from the PubChem database. Molecular docking study was performed for these natural compounds to evaluate and analyze their anti-lymphoma-cancer activity. A total of 16 compounds present in Vitex negundo, based on a comprehensive literature survey was selected for this molecular screening. Molecular docking analysis was carried out by Molegro Virtual Docker software, to screen the 16 chosen compounds and rank them according to their binding affinity towards the site of interaction of the oncoprotein, anaplastic lymphoma kinase. Out of the 16 screened phytocompounds, only 4 compounds showed promising interactions against the oncoprotein ALK (4ANL). 6’-p-hydroxybenzoyl mussaenosidic acid exhibited a very good binding with a molecular docking score of -127.723 kcal/mol, ranking first among the compounds screened. This was followed by Betulinic acid, Viridiflorol and protocatechuic acid with molecular docking scores of -95.596 kcal/mol, -76.1648 kcal/mol and -63.0854 kcal/mol and - respectively. The docking scores from the above study shows that the phytocompounds present in Vitex negundo extract exhibits an effective inhibitory effect against anaplastic lymphoma kinase protein that is over expressed in lymphoma.
Keywords
Anaplastic Lymphoma Kinase; In-Silico; Lymphoma; Molecular Docking; Medicinal Plant; Vitex Negundo
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| Copy the following to cite this article: Anusha D, Sharanya S, Ramya R, David D. C. Anticancer Screening of the Phytochemicals Present in the Medicinal Plant Vitex Negundo Against Mutant Anaplastic Lymphoma Kinase (ALK) Protein: An In-Silico Approach. Biomed Pharmacol J 2019;12(2). |
| Copy the following to cite this URL: Anusha D, Sharanya S, Ramya R, David D. C. Anticancer Screening of the Phytochemicals Present in the Medicinal Plant Vitex Negundo Against Mutant Anaplastic Lymphoma Kinase (ALK) Protein: An In-Silico Approach. Biomed Pharmacol J 2019;12(2). Biomed Pharmacol J 2019;12(2). Available from: https://bit.ly/2ZPmUh1 |
Introduction
Anaplastic lymphoma kinase is an enzyme that is active during the embryonic nervous system development of humans, but slowly loses its activity over the course of postnatal life.1 This enzyme is prone to various kinds of mutations notably chromosomal fusion. There are twenty such fusion proteins documented that are known to be involved predominantly in the pathogenesis of neuroblastoma, anaplastic large cell lymphomas and non- small cell lung cancer.2
The fusion proteins of the produced from the mutated anaplastic lymphoma kinase gene dimerize to activate the catalytic site of the ALK protein kinase domain, which leads to the activation of multiple cell proliferation pathways like Ras/Raf/MEK/ERK1/2 and the cell survival pathways like the JAK/STAT pathways.3
ALK was originally identified as an fusion oncogene nucleophosmin (NPM)-ALK resulting from a t (2,5) chromosomal translocation in ALCL .The fusion oncogene NPM-ALK is implicated in the pathogenesis of ALCL as it is detected in approximately 75% of all ALK-positive ALCL (6). Other ALK fusion genes, echinoderm microtubule-associated protein like 4 (EML4)- ALK is proven to be associated with non-small cell lung cancer (NSCLC).4
A number of ATP-competitive ALK inhibitors have been developed and have proven oncolytic activity against ALK positive cancer cells both in vitro and in vivo. Biologicals like Crizotinib, developed as an ALK inhibitor have gained FDA approval for ALK positive cancer in EML4-ALK positive NSCLC and ALCL.4
Few of these ALK inhibitors like Crizotinib (12) have advanced to the level of clinical trials5,6; Crizotinib recently gained FDA approval for ALK-positive cancers. It is used in the treatment of EML4-ALK-positive NSCLC but unfortunately like any other drugs it is also known to cause side effects. Hence, there is a need for the development of more potent and specific ALK inhibitors to reduce the adverse effects of the current drugs. In recent years, a number of ALK antagonists have appeared of which a set of novel and potent tetracyclic derivatives (6, 6-Dimethyl-11-oxo-6, 11- dihydro-5-H-benzo (b) carbazoles) (13–15) have been chosen for our present studies.7
Vitex negundo, a plant native to South and Southeast Asia, is an erect shrub or small tree growing from 2 to 8 m (6.6 to 26.2 ft) in height. Vitex is a genus of flowering plants from the family Lamiaceae. It has about 250 species.8 Species of Vitex are native throughout the tropics and subtropics and a few temperate regions.9 Almost all parts of this plant has immense medicinal value, ranging from antimicrobial, anti-cancer, anti-inflammatory, anti-ulcer activity etc. It is one of the tropical plants with immense medicinal properties.10
Methodology
The molecular docking software used is this study is molegro virtual software.
Lead Identification and optimization
A comprehensive search of all possible studies on Vitex negundo compounds was made by searching the electronic literature (PubMed database) for relevant published reports and by manual searching of reference lists of articles on this topic. A total of 16 ligands with antineoplastic attribute were selected based on electronic literature study of the compounds present in Vitex negando plant (Pub med database). The structures of these ligands were downloaded from the pubchem database.11
ADMET Prediction
Once the compounds were selected, elementary physical descriptors like number of hydrogen bond acceptors and donors, log P, molecular weight were calculated for the selected compounds using molinspiration. Using these parameters the compounds were then scanned for “Lipinski’s rile of 5”. The shortlisted compounds that follow “Lipinskis rule of 5” were then chosen for further study and analysis.11
Target Identification
Structure of G1269A Mutant Anaplastic Lymphoma Kinase (PDB ID: 4ANL) was chosen as our receptor target. This receptor protein was finalized based on literature study. ALK tyrosine k
