Novel Aglycones of Steroidal Glycoalkaloids as Potent Tyrosine Kinase Inhibitors: Role in VEGF and EGF Receptors Targeted Angiogenesis
TL;DR: The results for the first time report that these novel aglycones of GAs may be significant lead compounds in the development of new and effective multi-target antiangiogenic drugs with the least or no toxicity.
Abstract: Receptor tyrosine kinases (RTKs) are crucial targets in the pathway of angiogenesis and the currently used antiangiogenic drugs have limited efficiency with associated toxicity. In our continuous search for new and potent multitarget anti-angiogenic lead compounds, we have conducted in-silico interaction and inhibition studies of the selected aglycones of steroidal glycoalkaloids (GAs) and selected anti-angiogenic drugs, against the EGFR, VEGFR-1, VEGFR-2 using the AutoDock Tools 4.0 and other online bioinformatics softwares. The docking results have been interpreted in terms of binding energies (kcal/mol) and inhibition constant ( M). In our study, aglycones [solanidine (solanid-5-en-3 -ol), solasodine (Solasod-5-en-3 -ol) and tomatidine (5 -Tomatidan-3 -ol)] gave promising and comparable results with the antiangiogenic drugs (Gefitinib, Lapatinib, Axitinib and Motasenib). All the test aglycones expressed significant inhibition against RTKs under study, but tomatidine emerged as a most potent multi-target inhibitor of RTKs. The inhibition constant of tomatidine was observed almost 2-folds less compared to Gefitinib targeting against EGFR and 5-folds less to Axitinib, the standard drug against VEGFR-2. Moreover, these aglycones fulfilled the drug likeliness properties, when analyzed by Lipinski’s Rule of Five. In addition to this, the in-silico toxicity studies of aglycones remarkably showed no mutagenecity and tumorigenecity compared to the standard drugs. Our results for the first time report that these novel aglycones of GAs may be significant lead compounds in the development of new and effective multi-target antiangiogenic drugs with the least or no toxicity. In addition, the wet lab experiments are underway to support these in-silico
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TL;DR: It is proposed how nanoinformatics could hasten up the advancements in anticancer nanomedicines through use of computational tools, nanoparticles repositories & various modeling and simulation methods.
Abstract: Empowering role of nanoinformatics in design and elucidation of nanoparticles for effective cancer treatment has made this field a fascinating area for researchers, inspiring them to enhance up the quality and efficacy of existing anticancer medicines. Theoretical and computational modeling is being seen as a forefront solution for problems related to surface chemistry, optimized geometry, or other properties in nanoparticle designing and drug delivery. The current review aims to acquaint with the insight story of the incubation of in silico tools and techniques in nanotechnology to develop better anticancer nanomedicines. The review also recapitulates the assets and liabilities of this field and present an outline of existing inventiveness and endeavors of nanoinformatics. We propose how nanoinformatics could hasten up the advancements in anticancer nanomedicines through use of computational tools, nanoparticles repositories & various modeling and simulation methods.
13 citations
01 Jan 2013
TL;DR: Erysolin is a promising natural anticancer and anti-estrogenic agent and Feeble interactions with pro-apoptotic protein BAX, caspases 3 and 8 indicate possible involvement of extrinsic pathway in the erysolin-mediated apoptosis.
Abstract: Targeted therapy has been gaining momentum to be a promising strategy for drug development research. Natural compounds and their synthetic analogues have provided several promising anticancer drugs. Erysolin present in the Eruca sativa better known as rocket plant has been scarcely studied. In the present study, we assessed the anticancer potential and underlying mechanism(s) of action of erysolin in human breast cancer cell lines (MCF-7 and MDA-MB-231) using the in vitro and/or in silico experiments. Incubation of these cell lines with erysolin (10 and 50 µM) for 72 h resulted in 50-70% apoptosis in both cell lines at 50 µM with concomitant decrease in the cell viability. However, 10 µM erysolin induced 20% apoptosis in MDA-MB-231 cells while it was unresponsive in the MCF-7 cells. Further, our in silico results revealed significant interaction and better inhibition of erysolin to CDK2, CDK6, Bcl2 and ER-α compared to the standard reference compounds. Moreover, erysolin also showed higher affinity against interface of p53-MDM2 which might stimulate p53 in tumor cells or induces restoration of mutant p53 thereby making these cancer cells to undergo apoptosis. Feeble interactions with pro-apoptotic protein BAX, caspases 3 and 8 also indicate possible involvement of extrinsic pathway in the erysolin-mediated apoptosis. The results showed that erysolin is a promising natural anticancer and anti-estrogenic agent. Further, the in silico protocol for elucidating and validating apoptosis mechanism(s) by unknown compounds could also be used.
12 citations
Cites methods from "Novel Aglycones of Steroidal Glycoa..."
...Based on our previous studies[18-21], we tried to elucidate the mechanism of erysolin-induced apoptosis in the cell lines by an in silico approach using various molecular targets of apoptosis pathway....
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TL;DR: Results suggest that tomatidine could use as a potential candidate for cancer prevention and metastasis through the inhibitory effect on gelatinase.
11 citations
TL;DR: In silico validation of the wet lab data from aeroplysinin-1, curcumin and halofuginone using Autodock Tools 4.0 found the inhibition patterns of the vascular endothelial cell differentiation and capillary tube formation mediated by anti-angiogenic growth factors were found quite comparable with the in silico results using angiogenic targets.
Abstract: This study describes in silico validation of the wet lab data from aeroplysinin-1, curcumin and halofuginone using Autodock Tools 4.0. The inhibition patterns of the vascular endothelial cell differentiation and capillary tube formation mediated by anti-angiogenic growth factors from these test compounds were found quite comparable with the in silico results using angiogenic targets EFGR, bFGF and VEGFR-1. Successful validation of the wet lab results of the selected angiogenic targets by in silico method has led to exploit the hidden potential of in silico tools in preliminary screening of the unknown compounds for anti-angiogenic potential in a cost-effective manner.
8 citations
Cites background from "Novel Aglycones of Steroidal Glycoa..."
...Our recent publication further suggests that the in silico approach using molecular angiogenic targets could be used for preliminary screening to determine the anti-angiogenic potential of unknown compounds (Akhtar et al., 2011)....
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TL;DR: The study proposes that aglycones induce apoptosis by inhibiting the p53–MDM2 complex, p21Waf1/Cip1, and Bcl-2 proteins, which were even found comparable with the anticancer drugs nutlin and/or halofuginone.
Abstract: Exposure to exogenous and endogenous chemicals and subsequent cellular and molecular changes has been linked to enhanced cell proliferation and restricted apoptosis phenomenon. Though in the past decades numerous anticancer drugs inducing programmed cell death in cancer cells by targeting specific apoptotic markers have reached the market, they have been allied with unwanted side effects, ranging from mild to severe toxicity. With further understanding on the functional mechanism of p53 and MDM2 in apoptosis and in our continuous search for new and potent multi-target anticancer lead compounds, we have carried out molecular docking and inhibition studies of the selected aglycones along with selected anticancer leads, against the specific apoptotic and cell cycle markers using AutoDock Tools 4.0 and other computational softwares. The docking results have been analyzed in terms of binding energies (kcal/mol) and inhibition constant (µM). The study clearly proposes our aglycones [solanidine (Solanid-5-en-3β-ol), solasodine (Solasod-5-en-3β-ol), and tomatidine (5α-Tomatidan-3β-ol)] induce apoptosis by inhibiting the p53-MDM2 complex, p21Waf1/Cip1, and Bcl-2 proteins, which were even found comparable with the anticancer drugs nutlin and/or halofuginone. The work further emphasizes that the individual molecular targets such as BAX and Bcl-2 may result in misleading data at any level; however, ratio of responses to BAX and Bcl-2 shall be considered for better clue about a compound to be pro- or anti-apoptotic.
7 citations
Cites background from "Novel Aglycones of Steroidal Glycoa..."
...The a-solasodine [solasod-5-en-3b-ol] and atomatidine [5a-tomatidan-3b-ol], obtained from GA’s asolasonine and a-tomatine, form a part of spirosolane aglycones having a conventional steroidal frame with a spiro-azaketal functionality present in the side chain [17]....
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...cones of these GAs as potential anti-angiogenic leads [17, 23]....
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...In the current scenario, these aglycones stand in the forefront which being of natural origin and exhibiting good anti-angiogenic potential [17] have even proven good MDM2 inhibitors compared to the standard drugs at the in silico level [32, 34]....
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References
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TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
14,026 citations
TL;DR: It is shown that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckia genetic algorithm is the most efficient, reliable, and successful of the three.
Abstract: A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein)ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein)ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 y1 .
9,322 citations
"Novel Aglycones of Steroidal Glycoa..." refers methods in this paper
...0 [23-25], a suite of automated docking tool developed at the Scripps Research Institute, Molecular Graphics Laboratory, USA, which uses a genetic algorithm to find the binding conformations of the ligand (http://autodock....
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TL;DR: The latest version of DrugBank (release 2.0) has been expanded significantly over the previous release and contains 60% more FDA-approved small molecule and biotech drugs including 10% more ‘experimental’ drugs.
Abstract: DrugBank is a richly annotated resource that combines detailed drug data with comprehensive drug target and drug action information. Since its first release in 2006, DrugBank has been widely used to facilitate in silico drug target discovery, drug design, drug docking or screening, drug metabolism prediction, drug interaction prediction and general pharmaceutical education. The latest version of DrugBank (release 2.0) has been expanded significantly over the previous release. With approximately 4900 drug entries, it now contains 60% more FDA-approved small molecule and biotech drugs including 10% more 'experimental' drugs. Significantly, more protein target data has also been added to the database, with the latest version of DrugBank containing three times as many non-redundant protein or drug target sequences as before (1565 versus 524). Each DrugCard entry now contains more than 100 data fields with half of the information being devoted to drug/chemical data and the other half devoted to pharmacological, pharmacogenomic and molecular biological data. A number of new data fields, including food-drug interactions, drug-drug interactions and experimental ADME data have been added in response to numerous user requests. DrugBank has also significantly improved the power and simplicity of its structure query and text query searches. DrugBank is available at http://www.drugbank.ca.
2,380 citations
"Novel Aglycones of Steroidal Glycoa..." refers background or methods in this paper
...In addition to this, Sorafenib, marketed as Nexaver by Bayer Healthcare Pharmaceuticals showed clastogenecity, and was tested positive for mutagenesis in Ames test [4]....
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...Some of these drugs like Sorafenib were even clastogenic and mutagenic [4]....
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...1D), due to high early mortality rates [4,10]....
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...Lapatinib is administered to the patients along with Capecitabine which itself induces nausea, diarrhea and hand and foot syndrome [4,6]....
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...However, Pfizer Incorporated on January 30, 2009 discontinued the global phase III trial of Axitinib for which in combination with Gemcitabine showed no evidence of improved survival rates over treatments using Gemcitabine alone for advanced pancreatic cancer [4,7-9]....
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TL;DR: The Metropolis technique of conformation searching is combined with rapid energy evaluation using molecular affinity potentials to give an efficient procedure for docking substrates to macromolecules of known structure.
Abstract: The Metropolis technique of conformation searching is combined with rapid energy evaluation using molecular affinity potentials to give an efficient procedure for docking substrates to macromolecules of known structure. The procedure works well on a number of crystallographic test systems, functionally reproducing the observed binding modes of several substrates.
1,265 citations
"Novel Aglycones of Steroidal Glycoa..." refers methods in this paper
...0 [23-25], a suite of automated docking tool developed at the Scripps Research Institute, Molecular Graphics Laboratory, USA, which uses a genetic algorithm to find the binding conformations of the ligand (http://autodock....
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TL;DR: A set of web servers are presented to facilitate and optimize the utility of biological activity information within PubChem and provide tools for rapid data retrieval, integration and comparison of biological screening results, exploratory structure–activity analysis, and target selectivity examination.
Abstract: PubChem (http://pubchem.ncbi.nlm.nih.gov) is a public repository for biological properties of small molecules hosted by the US National Institutes of Health (NIH). PubChem BioAssay database currently contains biological test results for more than 700 000 compounds. The goal of PubChem is to make this information easily accessible to biomedical researchers. In this work, we present a set of web servers to facilitate and optimize the utility of biological activity information within PubChem. These web-based services provide tools for rapid data retrieval, integration and comparison of biological screening results, exploratory structure-activity analysis, and target selectivity examination. This article reviews these bioactivity analysis tools and discusses their uses. Most of the tools described in this work can be directly accessed at http://pubchem.ncbi.nlm.nih.gov/assay/. URLs for accessing other tools described in this work are specified individually.
1,138 citations
"Novel Aglycones of Steroidal Glycoa..." refers methods in this paper
...As for the preparation of ligands, the molecular formula and SMILES notations for the known drugs, steroidal GAs and their aglycones were obtained from Pubchem database [28] (http://pubchem....
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