Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell therapy (original) (raw)
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Current Computer-Aided Drug Design, 2017
Breast cancer is one of the biggest global dilemmas and its current therapy is to target the hormone receptors by the use of partial agonists/antagonists. potent drugs for breast cancer treatment are Tamoxifen, Trastuzumab, Paclitaxel, etc. which show adverse effects and resistance in patients. The aim of the study has been on certain phytochemicals which has potent actions on eRα, pR, eGfR and mtoR inhibition. the current study is performed by the use of molecular docking as protein-ligand interactions play a vital role in drug design. The 3D structures of ERα, pR, eGfR and mtoR were obtained from the protein data bank and docked with 23 3D PubChem structures of furanocoumarin compounds using FlexX. Drug-likeness property was checked by applying the Lipinski's rule of five on the furanocoumarins to evaluate anti-breast cancer activity. Antagonist and inhibition assay of eRα, eGfR and mtoR respectively has been performed using appropriate in-vitro techniques. The results confirm that Xanthotoxol has the best docking score for breast cancer followed by Bergapten, Angelicin, psoralen and isoimperatorin. further, the in-vitro results also validate the molecular docking analysis. this study suggests that the selected furanocoumarins can be further investigated and evaluated for breast cancer treatment and management strategies.
Molecular – Docking Studies of Potent Anticancer Agent
Journal of Computer Science & Systems Biology, 2012
Cyclin dependent kinases are critical molecules that control cell cycle progression from one phase to the other. However, mutational changes in these molecules lead to the purturbed cell cycle leading to uncontrolled cellular proliferation or cell death. In humans, mutations in cyclin dependent kinase 2 (1GII) is responsible for nearly 50% of cancers. In this paper preliminary in-silico screening were performed of natural polytriterpene phytochemical that are thought to have potential to inhibit mutated 1GII. Out of the two triterpenes boswellic acid and ursolic acid, boswellic acid shows inhibition activity with 1GII. From this study we propose that boswellic acid is promising towards oral cancer than ursolic acid.
Cell Death and Disease, 2016
Hedgehog (Hh) inhibitors have emerged as valid tools in the treatment of a wide range of cancers. Indeed, aberrant activation of the Hh pathway occurring either by ligand-dependent or-independent mechanisms is a key driver in tumorigenesis. The smoothened (Smo) receptor is one of the main upstream transducers of the Hh signaling and is a validated target for the development of anticancer compounds, as underlined by the FDA-approved Smo antagonist Vismodegib (GDC-0449/Erivedge) for the treatment of basal cell carcinoma. However, Smo mutations that confer constitutive activity and drug resistance have emerged during treatment with Vismodegib. For this reason, the development of new effective Hh inhibitors represents a major challenge for cancer therapy. Natural products have always represented a unique source of lead structures in drug discovery, and in recent years have been used to modulate the Hh pathway at multiple levels. Here, starting from an in house library of natural compounds and their derivatives, we discovered novel chemotypes of Hh inhibitors by mean of virtual screening against the crystallographic structure of Smo. Hh functional based assay identified the chalcone derivative 12 as the most effective Hh inhibitor within the test set. The chalcone 12 binds the Smo receptor and promotes the displacement of Bodipy-Cyclopamine in both Smo WT and drug-resistant Smo mutant. Our molecule stands as a promising Smo antagonist able to specifically impair the growth of Hh-dependent tumor cells in vitro and in vivo and medulloblastoma stem-like cells and potentially overcome the associated drug resistance.
Structural Chemistry, 2019
In a continuing effort to find new cytotoxic, antitumor, and less toxic agents from β-carbolines derivatives, using experimental and computational studies, five β-carboline alkaloids were tested in vitro for their cell growth inhibitory activity using Lepidium sativum phytotest. Then, molecular docking and correlation analysis between activity and structure study was performed to identify the interaction mode between these compounds and the colchicine binding site of tubulin. The experimental results revealed that harmaline and harmalol represent the most active compounds with IC 50 of 134.15 μg/mL and 239.43 μg/mL, respectively, lower than colchicine which is 248 μg/mL. The correlation analysis between activity and structure indicates that the hydroxy group and the partial hydrogenation of the pyridyl ring increase activity. Indeed, molecular docking analysis revealed that harmaline and harmalol have low binding energy and could interact, in particular through conventional hydrogen bonds and van der Waals interactions with the colchicine binding site of tubulin, indicating that harmaline and harmalol could have an antimitotic effect. Moreover, in silico analysis of ADME/Tox properties reveals that these molecules possess promising pharmacokinetic properties in terms of intestinal adsorption, volume of distribution, blood-brain barrier permeability and toxicity. The results obtained were used to design new harmaline derivative molecule, with promising results after a preliminary in silico evaluation. In summary, our results indicate that the β-carboline alkaloids studied have an in vitro and in silico antimitotic activity and their pharmacokinetic properties are promising and should be confirmed by an in vivo study.
International Research Journal of Multidisciplinary Technovation, 2021
There is a continuous requirement to develop novel, safe, effective and affordable anti-cancer drugs because Cancer is a serious disease at current situation. A huge number of patients die annually due to cancer disease. Phytochemical are the secondary metabolites of medicinal plants and significantly used in conventional cancer research. Bioactive phytochemical is favored as they claim differentially on cancer cell only without altering normal cell. Carcinogenesis is an intricate process and includes multifold signaling procedures. Phytochemical are pleiotropic in nature, function and target these events in multiple manners so they are considered as most appropriate candidate for drug development. The aim of the present research was to find out the anti-cancer activity of the phytochemical constituents through computer aided drug design approach. In this experiment, we have find total 42 natural compounds with anti-cancer activity against the cancer target 1QCF tyrosine kinase. T...
Docking Studies reveal Phytochemicals as the long searched Anticancer Drugs for Breast Cancer
Natural products including phytochemicals have been recently proposed as tumor suppressors. In this paper, docking study is presented to use these phytochemicals for their prospective role in cancers including breast and prostate cancer. The most common type of cancer in women all over the world is breast cancer. The breast cells including cancerous breast cells have receptors for binding with estrogen and progesterone to stimulate a growth response. This crucial property has been exploited to investigate binding properties of phytochemicals with these receptors to generate an antagonist response in order to resolve uncontrolled cancerous growth. The most commonly used breast cancer drugs mainly work against the effects of estrogen on these cells. In this context groups of different set of phytochemicals (3-IMG-Glucosinolates, Anthocyanins, Apigenin, Carnosol, Daidzein, Genistein, Isoflavones and Quercetin) were taken and docked into the active site of Human estrogen receptor (PDB ID: 2IOK). In this study, based on molecular docking, potential phytochemicals have successfully been identified which may be used as anticancer drugs against breast cancer. These studies based on binding energy, docking energy, drug likeness and other relevant scores show that Daidzein, Genistein and Quercetin could be the potential lead molecule for the inhibition of signals potent for Human breast cancer and Leu346, Leu384, Leu387, Phe404 and Leu525 are the most important residues for potential drug targets. This paper is the initial step towards a rational design of novel selective and potent Human estrogen inhibitors for the treatment of cancer.
Chemical approaches to targeting drug resistance in cancer stem cells
Drug discovery today, 2014
Cancer stem cells (CSCs) are a subpopulation of cancer cells with high clonogenic capacity and ability to reform parental tumors upon transplantation. Resistance to therapy has been shown for several types of CSC and, therefore, they have been proposed as the cause of tumor relapse. Consequently, much effort has been made to design molecules that can target CSCs specifically and sensitize them to therapy. In this review, we summarize the mechanisms underlying CSC resistance, the potential biological targets to overcome resistance and the chemical compounds showing activity against different types of CSC. The chemical compounds discussed here have been divided according to their origin: natural, natural-derived and synthetic compounds.
Multitargeted molecular docking study of phytochemicals on hepatocellular carcinoma
Journal of Applied Biology & Biotechnology
Hepatocellular carcinoma (HCC) is the fourth major cause of death worldwide, with a global diminishing survival rate of 19%. Irrespective of the advanced therapeutic strategies against this carcinoma, it persists as one of the most challenging diseases. Moreover, the low efficacy of existing treatment stratagem using synthetic drugs against HCC has led to the urgent investigation of natural alternatives that can result in a more efficient treatment with fewer health side effects than their synthetic counterparts. In this study, a total of 1259 phytochemicals were docked against 25 potential HCC protein targets with the help of PyRx, a virtual screening tool software. The pharmacokinetics and drug-like properties of these chemicals were examined through SWISS ADME webserver. Based on their binding affinity against each protein target, only 250 ligands were shortlisted further for toxicity analysis using the web tools ADMETlab 2.0 and Protox II. In accordance with the bioavailability radar and pharmacokinetic profile analysis, only two non-toxic phytochemicals: Sorgolactone and Alectrol, emerged as the most befitting drug candidates against HCC protein targets 6HH1 and 1ZXM, respectively. The findings of this study suggest that these two phytochemicals can be explored and exploited further for their use as potential HCC drug candidates.
2024
Breast cancer (BC) is the most commonly diagnosed cancer in women around the world. Several genetic mutations tend to induce the risk of BC progression. SPDEF (Sam pointed domain containing ETS transcription factor) is a prostate-derived ETS factor that maintains homeostasis, differentiation of epithelial tissues, and heritable alterations in cancer. Plant secondary metabolites like flavonoids, terpenoids, and alkaloids have shown anticarcinogenic effect in several literatures. Therefore, in this study the SPDEF protein was used as potential breast cancer therapeutic target. Pharmacokinetic properties (ADMET), drug-likeness, and molecular docking of the fifteen phytoconstituents were assessed against SPDEF protein by various in silico approaches. The results showed that genistein, 2-hydroxychalcone, ajoene, and allicin had no toxicity. As per toxicological endpoints prediction study, the median lethal dosage (LD50) values vary from 159 to 3919 mg/Kg. All of the phytoconstituents derivatives taken into account in this investigation, are projected to be good candidates for P-glycoprotein (p-gp). Using in silico methods, the fifteen phytoconstituents identified from the different plants were predicted for their inhibitory actions against SPDEF protein, suggesting their breast cancer therapeutic potential. Silibinin, codonolactone and genistein have showed the lowest binding energy (-7.7,-6.1 and-6.1 kcal/mol) respectively and predicted to have the best inhibitory effect against SPDEF protein. We selected these three phytoconstituents for molecular dynamic simulation at 200 ns. In a comparison analysis, the Silibinin-receptor complex structure qualifies for the maximum parameters. The predictions about the pharmacokinetic properties of these phytoconstituents would form the basis for future in vivo, and in vitro experiments to identify the most appropriate therapeutic compound.