Department Of Pharmaceutical Sciences and Natural Products
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Item Phytochemical investigation of natural sweetener from stevia rebaudiana (Bartoni)(Central University of Punjab, 2014) Mayank; Jaitak, VikasS. rebaudiana is an important plant because of the high concentration of steviol glycosides (SGs). Sugars and artificial sweeteners, which are used in general as well as in pharmaceutical field have shown multiple toxic effects. On the other hand SGs have shown sweetness profile many fold compared to sucrose along with many health benefits.The substitution of SGs as sweeteners seems to be a reasonable solution towards the safety issues. The antidiabetic activity of S. rebaudiana extract as well as SGs is well documented in literature. The association of diabetes with cancer is also well known factor. Taking in consideration the above mentioned factors we have investigated the anticancer potential of extracts of S. rebaudiana. Extracts was prepared using petrolieum ether, ethyl acetate, methanol, aqueous methanol and water. Three cell lines (A-549, H-460 and MCF-7) have been used to evaluate the anticancer potential using MTT assay. In case of A-549, MVE-5 showing IC50 value of 10 ?g/ml. Moreover, IC50 values of MVE-2 was also comparatively better and found to be less than 50 ?g/ml and MVE-4 had shown IC50 value of 90 ?g/ml. In case of H- 460 reasonably better IC50 have been observed for MVE-4 and MVE-5 which is 88 ?g/ml and 92 ?g/ml, respectively. In H-460 reasonably better IC50 have been observed for MVE-4 and MVE-5 which is 88 ?g/ml and 92 ?g/ml, respectively. But in case of MCF-7 breast cancer cell line MVE-1 and MVE-2 have shown IC50 value of 90 ?g/ml and 53 ?g/ml, respectively. Thus, various extracts have shown good antiproliferative activity and S. rebaudiana can be further investigated for its anticancer potential. Furthermore docking study on EGFR, v PI3K and mTOR receptor revealed that SGs have good binding affinity towards all the three mentioned receptors and can be suitably modified to explore its anticancer potential. Moreover unfavourable ADME profile can be overcome by structure modification. Thus on the basis of in-vitro and in-silico data we can conclude that S. rebaudiana extracts have promising anticancer potential. Further isolation of compounds have also been done successfully and total seven compounds have been isolated. Two compounds MVR-1 and MVR-5 have been successfully characterized and found to be quercetin and stevioside respectively which are already known compounds. Many reported SGs have shown poorer taste quality. Moreover taste quality of all SGs are different from one another. Thus docking studies were performed on SGs by constructing homology models of T1R2 and T1R3 subunits of human sweet taste receptors to explore the sweetness mechanism. Ramachandran plot, PROCHECK results and ERRAT overall quality factor indicated the acceptable quality of models. The binding pattern indicated that Asn 44, Ans 52, Ala 345, Pro 343, Ile 352, Gly 346, Gly 47, Ala 354, Ser 336, Thr 326 and Ser 329 are the main interacting amino acids residues of T1R2 and Arg 56, Glu105, Asp 215, Asp 216, Glu 148, Asp 258, Lys 255, Ser 104,Glu 217, Leu 51, Arg 52 of T1R3 respectively. Amino acids interact with SGs mainly by forming hydrogen bonds with hydroxyl group of glucose moieties. Maximum binding affinity has been obtained with SGs having total four glucose molecules attached with it and increase or decrease in glucose molecules reduced the binding afinityThere is significant variation in docked poses of all SGs. Taking in consideration the diverse binding patterns of various SGs as well as their structural features, we have proposed the mechanism of sweetness in the form of multiple point stimulation model. The present study will be helpful to know the proper mechanism of sweetness as well as binding patterns of SGs to sweet taste receptor. It will further helpful in understanding the difference in taste quality and will be used in improving the taste of SGs using semisynthetic approaches.Item Interaction model of steviol glycosides from Stevia rebaudiana (Bertoni) with sweet taste receptors: A computational approach(Elsevier Ltd, 2015) Mayank; Jaitak, Vikas; Mayank, Jaitak, V.Docking studies were performed on natural sweeteners from Stevia rebaudiana by constructing homology models of T1R2 and T1R3 subunits of human sweet taste receptors. Ramachandran plot, PROCHECK results and ERRAT overall quality factor were used to validate the quality of models. Furthermore, docking results of steviol glycosides (SG's) were correlated significantly with data available in the literature which enabled to predict the exact sweetness rank order of SG's. The binding pattern indicated that Asn 44, Ans 52, Ala 345, Pro 343, Ile 352, Gly 346, Gly 47, Ala 354, Ser 336, Thr 326 and Ser 329 are the main interacting amino acid residues in case of T1R2 and Arg 56, Glu 105, Asp 215, Asp 216, Glu 148, Asp 258, Lys 255, Ser 104, Glu 217, Leu 51, Arg 52 for T1R3, respectively. Amino acids interact with SG's mainly by forming hydrogen bonds with the hydroxyl group of glucose moieties. Significant variation in docked poses of all the SG's were found. In this study, we have proposed the mechanism of the sweetness of the SG's in the form of multiple point stimulation model by considering the diverse binding patterns of various SG's, as well as their structural features. It will give further insight in understanding the differences in the quality of taste and will be used to improve the taste of SG's using semi-synthetic approaches. ? 2015 Elsevier Ltd. All rights reserved.Item Indole derivatives as anticancer agents for breast cancer therapy: A review(Bentham Science Publishers B.V., 2016) Sidhu, Jagpreet Singh; Singla, Ramit; Mayank; Jaitak, VikasBreast cancer (BC) is the second most common cause of cancer-related deaths in women throughout the world. Multiple drugs have been approved by US-FDA for breast related malignancies. Frequent emergence of resistances creates the severe need of newer moieties that are free from such problems. Drugs targeting breast cancer have been observed to be based on the multiple mechanisms of action, and various indole based anticancer agents have also been explored. Moreover, indoles have promising anti-cancer potential; there has been the emphasis on the synthesis of indole derivatives to overcome problems faced by existing therapeutic agents. Taking into consideration the above-mentioned facts we have analyzed in detail the possible role of indole based anticancer agents typically for breast related malignancies. This is the first exhaustive review that jointly covers various synthetic anticancer indole derivatives and related signaling pathways by which these derivatives have shown promising anti-breast cancer potential. ? 2016 Bentham Science Publishers.Item Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell therapy.(Elsevier, 2015) Mayank; Jaitak, VikasCancer is responsible for millions of deaths throughout the world every year. Increased understanding as well as advancements in the therapeutic aspect seems suboptimal to restrict the huge deaths associated with cancer. The major cause responsible for this is high resistance as well as relapse rate associated with cancers. Several evidences indicated that cancer stem cells (CSC) are mainly responsible for the resistance and relapses associated with cancer. Furthermore, agents targeting a single protein seem to have higher chances of resistance than multitargeting drugs. According to the concept of network model, partial inhibition of multiple targets is more productive than single hit agents. Thus, by fusing both the premises that CSC and single hit anticancer drugs, both are responsible for cancer related resistances and screened alkaloids for the search of leads having CSC targeting ability as well as the capability to modulating multiple target proteins. The in silico experimental data indicated that emetine and cortistatin have the ability to modulate hedgehog (Hh) pathway by binding to sonic hedgehog (Hh), smoothened (Smo) and Gli protein, involved in maintenance CSCs. Furthermore, solamargine, solasonine and tylophorine are also seems to be good lead molecules targeting towards CSCs by modulating Hh pathway. Except solamargine and solasonine, other best lead molecules also showed acceptable in silico ADME profile. The predicted lead molecules can be suitably modified to get multitargeting CSC targeting agent to get rid of associate resistances.Item Drug target strategies in breast cancer treatment: Recent developments(Bentham Science Publishers B.V., 2014) Mayank; Jaitak, Vikas; Mayank, Jaitak, V.Breast cancer (BC) is the leading cause of death among women all over the world. Estrogen receptor (ER) based therapy is one of the major approaches to target BC and is associated with various problems such as primary as well as secondary resistance. ER signaling is a complex pathway as many factors are involved; including several types of ERs and their associated co-regulators. Increasing understanding of ER signals results in new approaches targeting towards BCs. In this context, ER co-regulators have been explored and many modulators of ER co-regulators have been found out. EGFR and mTOR pathways also have significant impact on BC endocrine therapy because of the complex crosstalk mechanism which is responsible for primary and secondary resistance. Triple negative breast cancer (TNBC) is majorly associated with BRCA mutations. Currently there is no approved targeted therapy available in such form of cancer. Although PARP inhibitors seem to be suitable candidates for it. The present review is focused on the current scenario of ER, EGFR, as well as mTOR signaling target therapy. We have also discussed the current status of PARP inhibitors in BC chemotherapy. ? 2014 Bentham Science Publishers.