Botany - Research Publications
Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/32
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Item Molecular docking and in vitro study of Syzygium cumini-derived natural compounds on receptor tyrosine kinases pathway components(Inderscience Enterprises Ltd., 2019) Singh, P; Bast, Felix; Bhushan, S; Mehra, R; Kamboj, P.Syzygium cumini (S. cumini) is used for a variety of biological activities such as anti-inflammatory, anti-diabetic and anti-oxidant; currently, it has been reported for DNA protecting activity against radiation damage. Receptor tyrosine kinases (RTKs) are identified as critical regulators of various cellular processes including cell proliferation, metabolism and apoptosis. These receptors have recently gained attention as an attractive target for cancer treatment. The present research was aimed to screen S. cumini-derived natural compounds against RTKs pathway components using molecular docking. Furthermore, in vitro anti-proliferative 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and anti-oxidative (nitro blue tetrazolium and H 2 CDFD) activities of leaf extract of S. cumini are also reported. Selected natural compounds were docked with X-ray crystal structure of RTKs signalling proteins using grid-based ligand docking with energetics Maestro 9.6. In the present investigation, our result highlighted that myricetin, kaempferol, delphinidin chloride, ellagic acid, rutin, petunidin, gossypol and mirtillin generated a good dock score with all selected proteins. Protein-ligand interactions accentuated that several bonds such as lipophilic, hydrogen bonding, π-π stacking and cation-π interactions represent a ruling contribution at the active site. Moreover, reduction in cell viability with leaf extract of S. cumini treatment at concentrations of 5-80 µg/ml after 48 h in MCF-7 cells was observed. Leaf extract of S. cumini significantly reduced the Reactive oxygen species (ROS) generation in MCF-7 cells after 48 h. These results indicate the anti-cancer potential of S. cumini. Thus, isolation and purification of anti-cancerous compounds are suggested to explore more possibilities in the field. © 2019 Inderscience Enterprises Ltd.Item Marine macroalga Caulerpa: role of its metabolites in modulating cancer signaling(Springer, 2019) Mehra, R; Bhushan, S; Bast, Felix; Singh, S.Cancer, the leading causes of death worldwide, causes multiple metabolic and physiological alterations, leading to an unregulated proliferation of cells. The existing anticancer therapies are usually nonspecific with side effects and or are extremely expensive, thus hunt for better therapeutics is still on, specially efforts are made to look for naturally occurring molecules. Sea harbors several organisms which are unexplored for their biological potentials. Green macroalga genus, Caulerpa, is one such invaluable repository of bioactive metabolites like alkaloids, terpenoids, flavonoids, steroids and tannins with reported bioactivities against many diseases including cancer. Anti-cancerous metabolites of Caulerpa like caulerpenyne (Cyn), caulerpin, caulersin, and racemosin C, possess unique structural moieties and are known to exhibit distinct effects on cancer cells. Theses metabolites are reported to affect microtubule dynamics, unfolded protein response, mitochondrial health, cell cycle progression, metabolic and stress pathways by their cross-talk with signalling proteins like AMPK, GRP78, GADD153, Bid, Bax, AIF, Bcl2, P21, cyclin D, cyclin E, caspase 9, and PTP1B. Targeting of multiple cancer hallmarks by Caulerpa metabolites, with concomitant modulations of multiple signalling cascades, displays its multifactorial approach against cancer. Evaluation of anti-cancer properties of this genus is particularly important as Caulerpa species are widely edible and utilized in several delicacies in the coastal countries. This is the first review article providing a consolidated information about the role of Caulerpa in cancer with major contributing metabolites and plausible modulations in cancer signaling and prospects. © 2019, Springer Nature B.V.Item Insilco Molecular Docking Study of Natural Compounds On Wild and Mutated Epidermal Growth Factor Receptor(Springer, 2014) Singh, Pushpendra; Bast, FelixThe role played by overexpression of tyrosine kinase epidermal growth factor receptor (EGFR), the transmembrane receptor central to numerous cellular processes comprising cell migration, adhesion, apoptosis, and cell proliferation, has been highlighted in various cancers such as prostate, breast, lung, and ovarian cancers as well as in mutations in the EGFR kinase domain. Although many therapeutic approaches have targetted EGFR, the mutations occurring in the EGFR kinase domain including L858 EGFR and T790/L858R had led to the amplification of EGFR signals, consequently leading to increased cell proliferation and cell growth. The strategies involving the inhibition of EGFR L858 and T790M have been accredited with limited achievement in addition to being associated with unwanted adverse effects as a result of crosstalk of wild-type EGFR. All current EGFR tyrosine kinase inhibitors have been identified as ATP competitive inhibitors of wild-type EGFR possessing aniline and quinazoline moiety on the ligands skeleton. Our results obtained by performing molecular docking study on Maestro 9.3 molecular docking suite indicated that CID5280343 possesses better energy conformation against wild-type EGFR as well as two mutated EGFR. Moreover, it was discovered in this study that the natural compounds CID72276, CID5280445, CID441794, and CID72277 and InterBioScreen's library STOCK1N-78657, STOCK1N-78976, and STOCK1N-78847 have better binding conformation against gatekeeper T790M mutated EGFR concluded to be brought about by means of flexible ligands/receptor-based molecular docking protocol. Miraculous features of these compounds are their various pharmacokinetic and pharmacodynamic parameters which were found to be satisfactory as drug-like molecules. This molecular docking study also summarizes docking free energy, protein-ligands interaction profile, and pharmacokinetic and pharmacodynamic parameter of lead molecules which were tremendously helpful in enhancing the activity of these natural compounds against EGFR.Item Caulerpa taxifolia inhibits cell proliferation and induces oxidative stress in breast cancer cells(Springer, 2018) Mehra, Richa; Bhushan, Satej; Yadav, Umesh Prasad; Bast, Felix; Singh, SandeepCaulerpa taxifolia (M. Vahl) C. Agardh or killer alga is known to possess several bioactive secondary metabolites with unique structural modifications. We investigated anti-oxidant and anti-proliferative activity of C. taxifolia extract (CTE) on breast and lung cancer cells, along with possible effects on mitochondrial membrane potential (MMP) and cell cycle progression. The results revealed up to 6-folds increase in reactive oxygen species (ROS), 2-folds increase in glutathione reductase (GR) activity, 1.7-fold increase in superoxide dismutase (SOD) activity and 1.8-fold change in catalase activity w.r.t. untreated cells i.e. 10.72 to 21.44 nmol/min/mL, 2.0 to 3.49 U/mL and 37.51 to 69.26 U/min/g FW, respectively, in MDA-MB-cells. Likewise, selective anti-proliferative activity with IC50 0.19 + 0.1, 0.27 + 0.1, and 0.43 + 0.1 μg/μL, was recorded in MDA-MB-231, T-47D, and H1299 cells. In addition, dose-dependent increase in MMP of up to 40% and G1/S phase mitotic arrest was documented by CTE treatment in MDA-MB-231 cells. The results suggest an anti-proliferative and oxidative stress inducing activity of CTE. Changes in MMP and cell cycle arrest further support the anti-cancer effects of CTE. It is believed that C. taxifolia may be considered as a potent source of anti-cancer drugs, subject to further validations.Item IMPACT OF PERSONALIZED MEDICINE IN CANCER(Nova Science Publishers, 2017) Singh, Pushpendra; Rani, Alka; Bast, FelixPersonalized medicine aims to customize therapeutic care based on a person's unique genetic profile. Physicians have tailored care based on individual's health history and the environment. However, the decoding of the human genome in 2003 was an important step towards breakthroughs in personalized medicine, as a clinical care that takes benefits of molecular tools to facilitate highly specific health care based on individual's unique genomic and molecular characteristics. Pharmacogenetics refers to a single gene that influences drug metabolism. However, pharmacogenomics encompasses all genes in the genome that may determine the drug response. Pharmacogenomics enables the improved understanding of disease pathogenesis through genomics research, via identification of new biomarkers for cancer diagnosis. Pharmacogenetics and pharmacogenomics are around to revolutionize the aspect of medicine; yet, many challenges stand in the way. Hike in the cost of genotyping make genetic profiling less attractive and its clinical implementation is also lagging far behind. This book chapter presents an overview of the opportunities and challenges that influence the participation of personalized approach of giving the right drug at the right dose to the right patient.Item In Silico and In Vitro Studies Evidenced Anticancer Natural Compounds, a Targeting Chemokine Receptor(iMedPub, 2016) Singh, Pushpendra; Bast, FelixChemokines are a family of small chemotactic cytokines, which play a significant role in lymphocyte homing to secondary lymphoid organs in addition to tumor growth and metastasis. Thus, inhibition of chemokine receptor caught attention for anticancer treatment strategy. We studied molecular docking of chemokines receptor CXCR2, CXCR4, and CCR5 against natural and marine compounds. All selected natural and marine compounds were docked with the X-ray crystal structure of CXCR2, CXCR4, and CCR5 retrieved from the PDB by using Maestro 9.6. Molecular docking was executed by the XP (extra precision) mode of GLIDE. On the basis of Gscore and protein-ligand interactions, top-ranking compounds were outlined. The docking study carried out to summarize the various Gscore, hydrophobic, electrostatic bond, hydrogen bond, π-cation and π-π interactions and oversee the protein-ligand interactions. Moreover, effect of Epigallocatechin-3-gallate (EGCG) on biological activity such as mRNA expression (CXCR2, CCR5, and Bid), cell proliferation, ROS, and cell-migration was reported after the 48 hrs treatments in MCF-7 cells. The RT-PCR densitometric bands analysis showed that compound EGCG reduced the mRNA expression of CXCR2, CCR5 and increased the Bid at 40 μM and 80 μM concentration. Moreover, EGCG significantly reduced cell proliferation, ROS generation and cell-migration after 48 hours treatments.Item Multitargeted molecular docking study of plant-derived natural products on phosphoinositide-3 kinase pathway components(Springer, 2014) Bast, Felix; Singh, PushpendraPhosphoinositide-3 kinase (PI3K) signaling pathway comprises of a cornucopia of protein molecules capable of regulating numerous cellular events, including cell survival, cell cycle regulation, angiogenesis, and apoptosis. Deregulation of PI3K downstream signaling is a phenomenon commonly seen in various types of cancer and also held responsible for poor prognosis and resistance to chemotherapy. Targeting PI3K signaling pathway has become a new and promising strategy in combating cancer. In the present study, PI3K signaling components PI3K, PDK1, Akt, and mTOR were chosen and 51 natural compounds along with 17 reference compounds were selected as ligand with the aid of PubMed published literature search. Ligands were docked to protein molecules by using Maestro 9.3 (Schrödinger Inc.). It was discovered in this study that compounds myricetin, quercetin, morin, luteolin, and emodin yielded excellent dock score with the proteins concluded with the help of docking free energy. The remarkable feature of these compounds are their various pharmacodynamics and pharmacokinetic characteristics, many of which are in accordance with the “Lipinski’s Rule of five”. The docking study carried out is an endeavor to portray the docking of these compounds with the proteins, to summarize the various Gscore, hydrogen bond, electrostatic bond, and to chart out various factors that are decisive for and also govern the protein–ligand interactions.Item Natural Compounds Targeting Transforming Growth Factor-β: In Silico and In Vitro Study(ejBio, 2016) Singh, Pushpendra; Bast, Felix; Singh, Ravi ShankarInhibition of the tumor-promoting effects of transforming growth factor beta receptor (TGFβR) in carcinogenesis provides a better therapeutic intervention. Various natural compounds, inhibitors of TGFβR have been used for in vitro and in vivo anticancer study. Although very few TGFβR inhibitors are now intensifying in preclinical studies. In this study our aim to investigate TGFβR1, TGFβR2 and TAK1 inhibitor by using molecular docking and in vitro study. Our result revealed that some compounds have better docking energy. Moreover, the effect of two lead molecules epigallocatechin gallate (EGCG) and myricetin on the mRNA expression of TGFβR1 was reported after the 48 hrs treatments in HepG2 and PC3 cancer cell lines. The RT-PCR showed that compound EGCG and myricetin reduced the mRNA expression of TGFβR1 at 80 μM concentration. This molecular docking study provides a better understanding of binding of compounds to the active site of proteins and to summarize the various binding energy, hydrophobic, hydrogen, an electrostatic bond that are decisive for the protein-ligand interactions. Further experimental work will be required for validation of our results.