Department Of Biochemistry And Microbial Sciences
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Item 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, ShashankApoptosis 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.Item 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, ShashankGamma 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.Item 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, ShashankThe 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.Item In Silico Identification of Novel Natural Inhibitors Of Carbohydrate Metabolic Pathway In Cancer Cells(Central University of Punjab, 2018) Dash, Swastika; Kumar, ShashankCarbohydrate metabolism in cancer cells is linked to the 'Warburg Effect' which states that, under aerobic conditions, cancer cells metabolize approximately ten fold more glucose to lactate in a given time than normal cells; typically altered glycolytic pathway regulation. This has made the blocking of glycolytic pathway enzymes, a fascinating strategy to find treatment for cancer. This project addresses in a comprehensive manner the main glycolytic enzymes accounting for high-rate glycolysis in cancer cells. In addition, highlights of inhibitors that can be used to target the particular enzymes to decrease proliferation have also been done. Furthermore, besides the known inhibitors, receptor-based molecular docking of certain methylated flavonoids was performed with the proteins (isozymes of carbohydrate metabolic pathway enzymes) to find the lead inhibitors. The proteins used in the study are GLUT1 (4PYP), Hexokinase2 (2NZT), Phosphofructokinase2 (2AXN), Pyruvate kinaseM2 (3GQY), Lactate dehydrogenase A (4AJP) and Enolase2 (5IDZ). The dock scores were in the range of -5.88 to -9.68 against different target proteins. The methylated flavonoids 2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-7-methoxy-4H-chromen- 4-one, 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-6,8-dimethoxy-4H-chromen-4- one, 2-(3,4-dimethylphenyl)-5,7-dimethyl-4H-chromen-4-one and 6-hydroxy-3,5,7,8- tetramethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one showed better dock scores for the target proteins in comparison to the standard inhibitors. Thus these methylated flavonoids might be considered promising leads for further development of glycolytic pathway inhibitors in cancer cells.