School Of Basic And Applied Sciences

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    Flavonoids as P-glycoprotein inhibitors for multidrug resistance in cancer: an in-silico approach
    (Taylor and Francis Ltd., 2022-09-19T00:00:00) Kumar, Amit; Kalra, Sourav; Jangid, Kailash; Jaitak, Vikas
    Cancer has become a leading cause of mortality due to non-communicable diseases after cardiovascular disease worldwide and is increasing day by day at a daunting pace. According to an estimate by 2040 there will be 28.4 million cancer cases. Occurrence of multidrug resistance has further worsened the scenario of available cancer treatment. Among different mechanisms of multidrug resistance efflux of xenobiotics by ABC transporter is of prime importance. P-glycoprotein (P-gp) is the major factor behind occurrence of multidrug resistance due to its wide distribution and invariably big binding cavity. Various generations of chemical inhibitors for P-gp have been designed and tested are not devoid of major side effects. Thus, in present study flavonoids a major class of natural compounds was virtually screened in order to find molecules which can be used as selective P-gp inhibitors to be used along with chemotherapeutics. After screening 4275 molecules from different classes of flavonoids i.e. flavan, flavanol, flavonone, flavone, anthocyanins, and isoflavone, through Glide docking top ten hit molecules were selected based on their binding affinity, binding energy calculation and pharmacokinetic properties. All the hit molecules were found to have docking score within the range of ?11.202 to ?9.699 kcal/mol showing very strong interaction with the amino acid residues of binding pocket. Whereas, dock score of standard P-gp inhibitor verapamil was ?4.984 kcal/mol. The ligand and protein complex were found to be quite stable while run through molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
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    Discovery of Natural Anti-Apoptotic Protein Inhibitor Using Molecular Docking and MM-GBSA Approach: An Anticancer Intervention
    (AMG Transcend Association, 2022-12-27T00:00:00) Dey, Sarbjit; Singh, Atul Kumar; Kumar, Shashank
    Apoptosis is a programmed molecular phenomenon in normal cells, and "evading apoptosis" is a hallmark of cancer. Overexpression of anti-apoptotic BCL-2 promotes cancer cell survival, leading to tumor formation, its maintenance and progression, and further chemoresistance. Therefore, BCL-2 is considered an exciting drug target in clinical studies. The Cip/Kip family protein p21, which acts as an inhibitor of cyclin-CDK complexes, can also exert anti-apoptotic function and thus be involved in cancer initiation and progression. Preliminary research suggests that Piper chaba phytochemical(s) possess anticancer activity, but the underlying mechanism is yet to be established. For the first time, we explored Piper chaba phytochemicals for their anti-apoptotic protein (BCL-2 and p21) inhibition potential using molecular docking and MM-GBSA experiments. UC2288 and Venetoclax were known standards for BCL-2 and p21 proteins, respectively. We also explored the pharmacokinetics and drug-likeness properties of lead molecules using the SwissADME web tool. A total of 45 P. chaba phytochemicals were identified from published literature and docked at the drug-binding site of target proteins. Chabamide F, Piperchabaoside B, Piperundecalidiene, and Chabamide G showed ? binding affinity (-9.0 kcal/mole) than UC2288, while Brachystamide B showed lower binding affinity (-9.7 kcal/mole) than Venetoclax. MM-GBSA results revealed Chabamide F has a higher binding affinity for p21 than the standard compound. Therefore, P. chaba phytoconstituents qualify for further experiments on the drug discovery process to target anti-apoptosis proteins in cancer cells. � 2022 by the authors.
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    Hesperidin potentially interacts with the catalytic site of gamma-secretase and modifies notch sensitive genes and cancer stemness marker expression in colon cancer cells and colonosphere
    (Taylor and Francis Ltd., 2022-10-14T00:00:00) Singh, Atul Kumar; Prajapati, Kumari Sunita; Kumar, Shashank
    Gamma secretase (GS) produces Notch Intracellular Domain (NICD) by trans-membrane cleavage of notch receptor. The NICD enters the nucleus and activates the notch signaling pathway (NSP) by activating notch-responsive gene transcription. Hyperactivation of NSP is related to cancer aggressiveness, therapy resistance, and poor therapy outcome, and decreased overall disease-free survival in patients. Till date, none of the GS inhibitors (GSI) has been clinically approved due to their toxicity in patients. Thus in the present study, we explored the GS catalytic site binding potential of hesperidin (natural flavone glycoside) and its effect on notch responsive gene expression in HCT-116 cells. Molecular docking, MM-GBSA binding energy calculations, and molecular dynamics (MD) simulation experiments were performed to study the GS catalytic site binding potential of hesperidin. The compound showed better GS catalytic site binding potential at the active site compared to experimentally validated GSI, N-N-(3, 5-Difluorophenacetyl)-L-alanyl-S-phenylglycine t-butyl ester (DAPT) in molecular docking and MM-GBSA experiments. MD simulation results showed that hesperidin forms stable and energetically favorable complex with gamma secretase in comparison to standard inhibitor (DAPT)-GS complex. Further, in�vitro experiments showed that hesperidin inhibited cell growth and sphere formation potential in HCT-116 cells. Further, hesperidin treatment altered notch responsive genes (Hes1, Hey1, and E-cad) and cancer stemness/self-renewal markers expression at transcription levels. In conclusion, hesperidin produces toxicity in HCT-116 cells and decreases colonosphere formation by inhibiting transcription of notch signaling pathway target genes and stemness markers. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
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    Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach
    (Frontiers Media S.A., 2021-08-12T00:00:00) Kushwaha, Prem Prakash; Singh, Atul Kumar; Bansal, Tanya; Yadav, Akansha; Prajapati, Kumari Sunita; Shuaib, Mohd; Kumar, Shashank
    The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS�3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential. � Copyright � 2021 Kushwaha, Singh, Bansal, Yadav, Prajapati, Shuaib and Kumar.