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      Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer

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          Abstract

          Withanolides are a group of pharmacologically active compounds present in most prodigal amounts in roots and leaves of Withania somnifera (Indian ginseng), one of the most important medicinal plants of Indian traditional practice of medicine. Withanolides are steroidal lactones (highly oxygenated C-28 phytochemicals) and have been reported to exhibit immunomodulatory, anticancer and other activities. In the present study, a quantitative structure activity relationship (QSAR) model was developed by a forward stepwise multiple linear regression method to predict the activity of withanolide analogs against human breast cancer. The most effective QSAR model for anticancer activity against the SK-Br-3 cell showed the best correlation with activity ( r 2=0.93 and rCV 2 =0.90). Similarly, cross-validation regression coefficient (rCV 2=0.85) of the best QSAR model against the MCF7/BUS cells showed a high correlation ( r 2=0.91). In particular, compounds CID_73621, CID_435144, CID_301751 and CID_3372729 have a marked antiproliferative activity against the MCF7/BUS cells, while 2,3-dihydrowithaferin A-3-beta- O-sulfate, withanolide 5, withanolide A, withaferin A, CID_10413139, CID_11294368, CID_53477765, CID_135887, CID_301751 and CID_3372729 have a high activity against the Sk-Br-3 cells compared to standard drugs 5-fluorouracil (5-FU) and camptothecin. Molecular docking was performed to study the binding conformations and different bonding behaviors, in order to reveal the plausible mechanism of action behind higher accumulation of active withanolide analogs with β-tubulin. The results of the present study may help in the designing of lead compound with improved activity.

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          Most cited references 37

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          Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review.

          The objective of this paper is to review the literature regarding Withania somnifera (ashwagandha, WS) a commonly used herb in Ayurvedic medicine. Specifically, the literature was reviewed for articles pertaining to chemical properties, therapeutic benefits, and toxicity. This review is in a narrative format and consists of all publications relevant to ashwagandha that were identified by the authors through a systematic search of major computerized medical databases; no statistical pooling of results or evaluation of the quality of the studies was performed due to the widely different methods employed by each study. Studies indicate ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoietic, and rejuvenating properties. It also appears to exert a positive influence on the endocrine, cardiopulmonary, and central nervous systems. The mechanisms of action for these properties are not fully understood. Toxicity studies reveal that ashwagandha appears to be a safe compound. Preliminary studies have found various constituents of ashwagandha exhibit a variety of therapeutic effects with little or no associated toxicity. These results are very encouraging and indicate this herb should be studied more extensively to confirm these results and reveal other potential therapeutic effects. Clinical trials using ashwagandha for a variety of conditions should also be conducted.
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            Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo.

            Withaferin A (WA) is derived from the medicinal plant Withania somnifera, which has been safely used for centuries in Indian Ayurvedic medicine for treatment of different ailments. We now show, for the first time, that WA exhibits significant activity against human breast cancer cells in culture and in vivo. The WA treatment decreased viability of MCF-7 (estrogen-responsive) and MDA-MB-231 (estrogen-independent) human breast cancer cells in a concentration-dependent manner. The WA-mediated suppression of breast cancer cell viability correlated with apoptosis induction characterized by DNA condensation, cytoplasmic histone-associated DNA fragmentation, and cleavage of poly-(ADP-ribose)-polymerase. On the other hand, a spontaneously immortalized normal mammary epithelial cell line (MCF-10A) was relatively more resistant to WA-induced apoptosis compared with breast cancer cells. The WA-mediated apoptosis was accompanied by induction of Bim-s and Bim-L in MCF-7 cells and induction of Bim-s and Bim-EL isoforms in MDA-MB-231 cells. The cytoplasmic histone-associated DNA fragmentation resulting from WA exposure was significantly attenuated by knockdown of protein levels of Bim and its transcriptional regulator FOXO3a in both cell lines. Moreover, FOXO3a knockdown conferred marked protection against WA-mediated induction of Bim-s expression. The growth of MDA-MB-231 cells implanted in female nude mice was significantly retarded by 5 weekly i.p. injections of 4 mg WA/kg body weight. The tumors from WA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumors from control mice. These results point toward an important role of FOXO3a and Bim in regulation of WA-mediated apoptosis in human breast cancer cells.
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              Molecular insight in the multifunctional activities of Withaferin A.

              Herbal medicine which involves the use of plants for their medicinal value, dates as far back as the origin of mankind and demonstrates an array of applications including cardiovascular protection and anti-cancer activities, via antioxidant, anti-inflammatory and metabolic activities. Even today the popularity of medicinal herbs is still growing like in traditional medicines such as the Indian medicine, Ayurveda. One of the Ayurvedic medicinal plants is Withania somnifera Dunal, of which the important constituents are the withanolides. Among them, Withaferin A is one of the most bioactive compounds, exerting anti-inflammatory, pro-apoptotic but also anti-invasive and anti-angiogenic effects. In the context of modern pharmacology, a better insight in the underlying mechanism of the broad range of bioactivities exerted by Withaferin A is compulsory. Therefore, a lot of effort was made to explore the intracellular effects of Withaferin A and to characterize its target proteins. This review provides a decisive insight on the molecular basis of the health-promoting potential of Withaferin A. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                22 June 2017
                : 11
                : 1859-1870
                Affiliations
                [1 ]Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea
                [2 ]Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Babu Banarasi Das Northern India Institute of Technology, Lucknow
                [3 ]Department of Bioinformatics, Indian Council of Medical Research, New Delhi
                [4 ]Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur
                [5 ]Metabolic & Structural Biology Department, CSIR–Central Institute of Medicinal & Aromatic Plant, Lucknow, India
                Author notes
                Correspondence: Dharmendra K Yadav, College of Pharmacy, Gachon University, Hambakmoeiro 191, Yeonsu-gu, Incheon City, 406-799, Korea, Tel +82 32 820 4947, Email dharmendra30oct@ 123456gmail.com
                Feroz Khan, Metabolic & Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.-CIMAP, Kukrail Picnic Spot Road, Lucknow, 226015, India, Tel +91 522 271 8668, Email f.khan@ 123456cimap.res.in
                Article
                dddt-11-1859
                10.2147/DDDT.S130601
                5491705
                © 2017 Yadav et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                admet, breast cancer, qsar, molecular docking, withanolides

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