Botany - Research Publications
Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/32
Browse
13 results
Search Results
Item Insilco Molecular Docking Study Of Natural Compounds On Wild and Mutated Epidermal Growth Factor Receptor.(2014) Singh, Pushpendra; Bast, Felix.Item Homology modeling of chemokine CCR7, molecular docking, and in vitro studies evidenced plausible immunotherapeutic anticancer natural compounds(Birkhauser Boston, 2016) Singh, Pushpendra; Singh, Ravi Shankar; Rani, Alka; Bast, FelixThe chemokine receptor 7 is a G-protein coupled, receptors coordinates the migration of cancer cells towards CCL19 and CCL21 constitutively expressed lymphatic organs. Chemokine receptor 7 facilitates cancer progression by generating new lymphatic vessels that serve as conduits for tumor dissemination to lymph nodes. In this context, chemokine receptor 7 inhibitor recently caught an attention for cancer cell growth inhibitor. The 3-D crystalline structure of chemokine receptor 7 not available in protein data bank (PDB), first we predicted the 3-D structure of chemokine receptor 7 and then performed receptor-based molecular docking of chemokine receptor 7 against natural and marine compounds. Semiquantitative polymerase chain reaction (PCR) and quantitative real-time PCR were performed for mRNA expression of chemokine receptor 7 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) used as internal control. The best-docked compounds have been selected for chemokine receptor 7 inhibitors by optimal energy value (Gscore), types of interactions, and conformations. CID6441009, 42607750, 72276, 6711419, 56835050, 65064, 23663412, 72277, 643668, 54679285 compound have a better binding energy ?11.35, ?10.51, ?10.16, ?9.98, ?9.95, ?9.86, ?9.83, ?9.57, ?9.47, and ?9.45 respectively against chemokine receptor 7. Protein?ligand interactions profile highlighted that amino acid Glu45, Lys50, Arg54, Lys57, Trp114, Met260, Glu205, Gln227, Gln276, and Asp309 involved in the hydrophobic, hydrogen bonding, and ?-? stacking interactions play a central role at the active site. Moreover, treatment with the Epigallocatechin gallate led to down-regulation of mRNA expression of chemokine receptor 7 in HepG2 and PC3 cells. This molecular docking study recapitulates the docking free energy, protein?ligands interactions profile, pharmacokinetic, and the pharmacodynamic parameter of lead molecules, which are extremely helpful to improve the activity of natural and marine compounds against chemokine receptor 7. ? 2016, Springer Science+Business Media New York.Item Molecular Docking Study of Natural Compounds against Non Receptor Protein Tyrosine Kinases Src(Pharma Scholars Library, 2015) Bast, Felix; Singh, PushpendraNon-receptor tyrosine kinases Src family plays an important role in signal transduction induced by diverse extracellular stimulus, including cytokine, and growth factors. Overactivity or overexpression of the non-receptor tyrosine kinase Src is involved in the growth, development and progression of various human cancers and their inhibitors are under intensive investigations as novel anti-cancer agents. Therefore, we studied receptor-based molecular docking of src against natural compounds. Each Selected compounds docked with the X-ray crystal structure of Src (PDB; 3EL7). The best-docked compounds have been elected for target by optimal energy value, types of interactions, and conformations. STOCK1N-75795, STOCK1N-80087, STOCK1N-72227, STOCK1N-79428, STOCK1N-72232, STOCK1N-72129, and STOCK1N-72552 compound have a better binding energy as well as binding conformation against src. Foremost, STOCK1N-80087, STOCK1N-72227, and STOCK1N-72232 are their excellent QPlogPo/w, CIQPlogS, QPlog HERG K+ channels, QPPCaco, QPlogBB, QPPMDCK, QPlogKP, QPlogKhsa and percentage of human oral absorption values which satisfy the Lipinski’s Rule of Five. This molecular docking study recapitulates docking free energy, protein ligands interaction profile, pharmacokinetic, and pharmacodynamic parameter of lead molecules, which are tremendously helpful to improve activity of natural compounds against src.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 INFLUENCE OF INSULIN AND METFORMIN ON PROSTATE CANCER(Nova Science Publishers, 2017) Singh, Pushpendra; Bast, Felix; Kumar, Shashank; Saini, Khem ChandDietary habit and hormonal factor play a significant role in prostate cancer deregulation in addition to genetic and environmental factor. Nonandrogenic growth factor like insulin and insulin growth factor are influences the prostate cancer initiation and progression. Insulin and Insulin-like growth factor regulate various metabolic pathways, cell growth, cellular proliferation and apoptosis. Various epidemiological results point out that insulin not only increased the risk of cardiovascular, macrovascular, and microvascular complications but also at significantly increase the risk of various cancers. The use of metformin, the usually approved drug for type 2 diabetes, was continually linked with the decreased risk of the incidence of a variety of cancers. More than 60 clinical trials of metformin being tested as a treatment for various types of cancer, including breast, colon, prostate, endometrial, and pancreatic cancer. The ability of metformin to lower circulating insulin may be predominantly imperative for the treatment of cancers. Moreover, metformin inhibiting mammalian target of rapamycin promoted cell growth signaling. In this chapter, the confirmation behind a role for metformin in cancer therapy and its prospective molecular mechanisms of action are discussed.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 Screening and biological evaluation of myricetin as a multiple target inhibitor insulin, epidermal growth factor, and androgen receptor; In silico and in vitro(Springer New York LLC, 2015) Singh, Pushpendra; Bast, FelixMyricetin is a naturally omnipresent benzo-?-pyrone flavonoids derivative; has potent anticancer activity. Receptor tyrosine kinases family provides the decisive role in cancer initiation and progression. These receptors have recently caught the attention of the researchers as an attractive target to combat cancer, owing to the evidences endorsed their over-expression on cancer cells. This study is a concerted effort to explore the potent and specific multi-targeted inhibitor against RTKs and AR\ER employing molecular docking approach. IR, IGF1R, EGFR, VEGFR1, VEGFR2, and AR\ER were chosen as a protein and natural compounds as a ligand. Molecular docking procedure followed by using Maestro 9.6 (Schr?dinger Inc). All natural compounds were docked with the X-ray crystal structures of selected proteins by employing grid-based ligand docking with energetics Maestro 9.6. IBS natural compounds docked with each selected protein molecules by using GLIDE high throughput virtual screening. On the basis of Gscore, we selected 20 compounds from IBS (50,000 compounds) along with 68 anticancer compounds from published literature for GLIDE extra precision molecular docking. Calculated docking free energy yielded the excellent dock score for the myricetin when docked with proteins EGFR, IR, and AR\ER. Protein-ligand interactions profile highlighted that the lipophilic, hydrogen bonding and ?-? stacking interactions play a central role in protein-ligand interactions at the active site. The results of MTT assay reveal that the myricetin inhibit the viability and proliferation of cancer cells in a dose-dependent manner. Treatment with the myricetin led to down-regulation of mRNA expression of EGFR, IR, mTOR, and Bcl-2. Although, further in vitro and in vivo experimental studies are required for the experimental validation of our findings. ? 2015 Springer Science+Business Media New York.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 In silico molecular docking study of natural compounds on wild and mutated epidermal growth factor receptor(Birkhauser Boston, 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. ? 2014 Springer Science+Business Media New York.Item High-throughput virtual screening, identification and in vitro biological evaluation of novel inhibitors of signal transducer and activator of transcription 3(Birkhauser Boston, 2015) Singh, Pushpendra; Bast, FelixSignal transducer and activator of transcription (STAT) family, encompassing protein molecules that function as a second messenger and transcription factor, are famously known to regulate a multitude of cellular processes including inflammation, cell proliferation, invasion, angiogenesis, metastasis and immune system homeostasis. STAT3 is one of the six members of a family of transcription factors. STAT3 has proved themselves to be interesting candidates for anticancer therapy as they are over-expressed in most cancer cells. Thus, we studied receptor-based molecular docking of STAT3 against natural compounds and further validations of lead molecules in an array of cancer cells. In the present study, we screened approximately 50,000 natural compounds from the IBS. All natural compounds were docked with the X-ray crystal structure of STAT3 (PDB; 1BG1) retrieved from the protein data bank by using Maestro 9.6 (Schr?dinger Inc). First, we performed high-throughput virtual screening of IBS against the SH2 domain of STAT3. Further, best 20 compounds that possess minimal Gscore along with 85 natural compounds that had been reported in published literature as having anticancer properties were selected, and molecular docking was performed using the XP (extra precision) mode of GLIDE. We analyzed Gscore and protein-ligand interactions of top ranking compounds. It was discovered in this study, compounds CID252682, CID5281670 (Morin), CID5281672 (Myricetin), CID72277 (Epigallocatechol) and CID65064 (Epigallocatechin Gallate, EGCG) yielded the excellent dock score with the STAT3 concluded with the help of docking-free energy. Moreover, IBS STOCK1N-43090, STOCK1N-66505, STOCK1N-54303, STOCK1N-44634, STOCK1N-45027, STOCK1N-73784, STOCK1N-69597, STOCK1N-73062, STOCK1N-81915 and STOCK1N-70844 have better docking-free energy. Further, we chose EGCG and myricetin compounds, and their effect on biological activity such as cell proliferation, oxidative stress, colony formation, mRNA expression of STAT3, and cell number was reported after the 48 h treatments in cancer cell lines. EGCG and myricetin reduce the STAT3 mRNA expression confirmed by RTPCR. Moreover, EGCG and myricetin reduce cell proliferation and ROS generation after 48 h treatments. Interestingly, our result also indicates that the reduction in potential for colony formation enhances anti-metastasis activity of EGCG and myricetin. The information obtained from our study assisted us in drawing a more lucid picture regarding the existence STAT3 natural compounds inhibitor on diverse cancer cells. ? 2015 Springer Science+Business Media.