Browsing by Author "Mishra, Abha"
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Publication Catechin isolated from faba beans (Vicia faba L.): insights from oxidative stress and hypoglycemic effect in yeast cells through confocal microscopy, flow cytometry, and in silico strategy(Taylor and Francis Ltd., 2022) Choudhary, Dhiraj Kumar; Chaturvedi, Navaneet; Singh, Amit; Mishra, AbhaThe present aim of this investigation was to evaluate the effect of catechin from faba beans on oxidative stress and glucose uptake in yeast cells. Flow cytometry approach indicated that 2-NBDG (1.98 � 0.37) seed extract had a lower relative fluorescence signal than methanol (5.98 � 0.67) and acetone seed extract (4.43 � 0.55). In comparison to the control and seed extract, H2O2 exposure increased the apoptosis rate of yeast cells from 8.20% to 64.80%. Yeast cells incubated with H2O2 produced significantly more ROS intensity (162 � 4.32, p < 0.05) than control cells (118 � 2.52, p < 0.05) and less than seed extract-treated cells. Molecular dynamics simulation studies were performed for cat:?-amylase (catechin-?-amylase complex) which revealed the stable and mixed mode of inhibition during a simulation. The synergistic action of polyphenols or catechin present in seed extract may be responsible for the anti-oxidative stress and hypoglycaemic effects. The findings of this study may provide insight into the further development of a novel antidiabetic drug for T2DM. Communicated by Ramaswamy H. Sarma. � 2021 Informa UK Limited, trading as Taylor & Francis Group.Publication Discovery of Histone Deacetylase Inhibitor Using Molecular Modeling and Free Energy Calculations(American Chemical Society, 2022) Mishra, Abha; Singh, AmitThe histone acetylation-deacetylation at lysine regulates the functions of many cellular proteins. An increased expression of HDAC6 can cause an increased amount of deacetylated histones, which leads to an inhibition of gene expression and has been associated with cancer cell proliferation. The present study screened the ZINC database to find novel HDAC6 inhibitors using virtual high-throughput screening techniques. The docking score, free energy, and binding pattern of the complexes were used to select a best ligand for further study. Molecular dynamic simulations, binding interactions, and the stability of docked conformations were investigated. Several parameters that determine protein-ligand interactions, such as root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and binding pattern, were observed. Hydrogen bonds were observed at His 573 and Gly 582 after a 150 ns simulation with identified compound ZINC000002845205, and they were similar to known inhibitor Panobinostat. The molecular mechanics with generalised Born and surface area solvation (MM/GBSA) free energy was comparable to known inhibitor Panobinostat. ZINC000002845205 qualifies drug-likeness according to Lipinski's rule-of-five, rule-of-three, and the World Drug Index (WDI)-like rule, but there is one violation in the lead-like rule. � 2022 The Authors.Publication Discovery of the allosteric inhibitor from actinomyces metabolites to target EGFRCSTMLR mutant protein: molecular modeling and free energy approach(Nature Research, 2023) Saini, Ravi; Kumari, Sonali; Bhatnagar, Aditi; Singh, Amit; Mishra, AbhaEGFR (epidermal growth factor receptor), a surface protein on the cell, belongs to the tyrosine kinase family, responsible for cell growth and proliferation. Overexpression or mutation in the EGFR gene leads to various types of cancer, i.e., non-small cell lung cancer, breast, and pancreatic cancer. Bioactive molecules identified in this genre were also an essential source of encouragement for researchers who accomplished the design and synthesis of novel compounds with anticancer properties. World Health Organization (WHO) report states that antibiotic resistance is one of the most severe risks to global well-being, food safety, and development. The world needs to take steps to lessen this danger, such as developing new antibiotics and regulating their use. In this study, 6524 compounds derived from�Streptomyces�sp. were subjected to drug-likeness filters, molecular docking, and molecular dynamic simulation for 1000�ns to find new triple mutant EGFRCSTMLR (EGFR-L858R/T790M/C797S) inhibitors. Docking outcomes revealed that five compounds showed better binding affinity (? 9.074 to ? 9.3�kcal/mol) than both reference drug CH7233163 (? 6.11�kcal/mol) and co-crystallized ligand Osimertinib (? 8.07�kcal/mol). Further, molecular dynamic simulation confirmed that ligand C_42 exhibited the best interaction at the active site of EGFR protein and comprised a better average radius of gyration (3.87��) and average SASA (Solvent Accessible Surface Area) (82.91 �2) value than co-crystallized ligand (4.49��, 222.38 �2). Additionally, its average RMSD (Root Mean Square Deviation) (3.25��) and RMSF (Root Mean Square Fluctuation) (1.54��) values were highly similar to co-crystallized ligand (3.07��, 1.54��). Compared to the reference ligand, it also demonstrated conserved H-bond interactions with the residues MET_793 and GLN_791 with strong interaction probability. In conclusion, we have found a potential drug with no violation of the rule of three, Lipinski's rule of five, and 26 other vital parameters having great potential in medicinal and pharmaceutical industries applications and can overcome synthetic drug issues. � 2023, The Author(s).Publication Fisetin 8-C-glucoside as entry inhibitor in SARS CoV-2 infection: molecular modelling study(Taylor and Francis Ltd., 2022) Mishra, Abha; Kaur, Upinder; Singh, AmitCoronaviruses are RNA viruses that infect varied species including humans. TMPRSS2 is gateway for SARS CoV-2 entry into the host cell. It causes proteolytic activation of spike protein and discharge of the peptide into host cell. The TMPRSS2 inhibition could be one of the approaches to stop the viral entry, therefore, interaction pattern and binding energies for Fisetin and TMPRSS2 have been explored in the present study. TMPRSS2 peptide was used for homology modelling and then for further study. Molecular docking score and MMGBSA Binding energy of Fisetin was better than Nafamostat, a known inhibitor of TMPRSS2. Post docking MM-GBSA free energy for Fisetin and Nafamostat was ?42.78 and ?21.11 kcal/mol, respectively. Fisetin forms H bond with Val 25, His 41, Lys 42, Lys 45, Glu 44, Ser186. Nafamostat formed H bonds with Lys 85, Asp 90, Asp 203. RMSD plots of TMPRSS2, TMPRSS2-Fisetin and TMPRSS2-Nafamostat complex showed stable profile with very small fluctuation during entire simulation of 150 ns. Significant decrease in TMPRSS2-Fisetin and TMPRSS2-Nafamostat complex fluctuation occurred around His 41, Glu 44, Gly 136, Ser 186 in RMSF study. During simulation Fisetin interaction was observed with residues Val 25, His 41, Glu 44, Lys 45, Lys 87, Gly 136, Gln 183, Ser 186 likewise interaction of Nafamostat with Lys 85, Asp 90, Asn 163, Asp 203 and Ser 205. Post simulation MM-GBSA free energy was found to be ?51.87 � 4.3 and ?48.23 � 4.39 kcal/mol for TMPRSS2 with Fisetin and Nafamostat, respectively. Communicated by Ramaswamy H. Sarma. � 2020 Informa UK Limited, trading as Taylor & Francis Group.Publication Green synthesis of nanoparticles by endophytes(Elsevier, 2022) Mishra, Abha; Bhatnagar, AditiA few years ago, there was limited knowledge about the benefits of endophytes. They were known to help host plants fight their daily biotic and abiotic stresses. Additionally, they acted as natural insecticides, aided in growth, and supplying nutrients to them. At present, endophytes have an all-new dimension added to them, benefiting their hosts and humans simultaneously. Nowadays, endophytes are being used in nanotechnology to build nanomaterials to enhance various existing medicinal and nonmedicinal products. The traditional process of making nanoparticles is exhausting and cost-ineffective, whereas using green chemistry synthesis mechanisms to produce functionally viable nanoparticles is an excellent approach. In this chapter, various approaches for producing different nanoparticles from endophytes are discussed along with their uses. � 2023 Elsevier Inc. All rights reserved.Publication Investigation of molecular mechanism leading to gefitinib and osimertinib resistance against EGFR tyrosine kinase: molecular dynamics and binding free energy calculation(Taylor and Francis Ltd., 2023) Singh, Amit; Mishra, AbhaTyrosine kinase (TK) is an important protein responsible for phosphorylation of variety of proteins that helps in signal transduction process in transferring signal to regulate various physiological and biochemical processes. Drugs inhibiting signal transduction pathways can be a very rational approach to inhibit cellular physiological and biochemical process. Tyrosine kinase inhibitors are a wide family of drugs that have been used successfully in cancer chemotherapy. Certain mutations around the catalytic cleft may cause conformational changes at binding site and leads to decrease in inhibitor sensitivity to TK mutants. EGFRT790M mutation is the first recognized acquired resistance after tyrosine kinase inhibitor therapy that leads to resistant to first generation TKI in about 50% of non-small cell lung carcinoma patients. Third generation EGFR-TKIs bind irreversibly to the C797, which is present in the ATP-binding pocket. The present work provides a molecular mechanism for understanding the Gefitinib and Osimertinib sensitivities with the EGFRWILD, EGFRL858R, EGFRT790M, EGFRT790M+C797S mutants using molecular modelling techniques. Changes in response against Gefitinib and Osimertinib were observed with the change of amino acids at the tyrosine kinase domain of EGFRWILD and its mutants (EGFRL858R, EGFRT790M, EGFRT790M+C797S). RMSD, RMSF and binding energies calculation well correlates with the change in clinical observation. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.Publication Leucoefdin a potential inhibitor against SARS CoV-2 Mpro(Taylor and Francis Ltd., 2021) Singh, Amit; Mishra, AbhaLeucoefdin an important constituent of various fruits such as banana, raspberry, etc. was explored to target MPro protease of SARS Co-V 2. Ligand was found to bind at active site of MPro with large negative binding energies in molecular docking and simulation study. The docking results showed that Leucoefdin interacted with the MPro by forming hydrogen bonds, at Leu 141, His163, His 164, and Glu 166. Other non-bonded interactions were seen at Met49, Pro52, Tyr54, Phe140, Leu141, Cys145 and Met165. Results of Leucoefdin was in coherence with the recently reported MPro protease-inhibitor complex. It even displayed better binding energies (kcal/mol) in HTVS (-6.28), SP (-7.28), XP (-9.29) and MMGBSA (-44.71) as compared to the reference ligand [HTVS (-4.87), SP (-6.79), XP (-5.75) and MMGBSA (-47.76)]. Leucoefdin-MPro complex on molecular dynamic simulation showed initial fluctuations in RMSD plot for a certain period and attained equilibrium which remained stable during entire simulation for 150 ns. RMSF of protein showed less secondary structure fluctuations and a greater number of H-bond formation with Leucoefdin during 150 ns simulation. Post simulation MMGBSA analysis showed binding energy of -45.98 Kcal/mol. These findings indicated the potential of Leucoefdin as lead compound in R&D for drug discovery and development against SARS CoV-2. Communicated by Ramaswamy H. Sarma. � 2020 Informa UK Limited, trading as Taylor & Francis Group.Publication Molecular dynamics simulation and free energy calculation studies of Coagulin L as dipeptidyl peptidase-4 inhibitor(Taylor and Francis Ltd., 2022) Singh, Amit; Mishra, AbhaPlant derived product can be used as other alternatives to currently used drugs for controlling chronic diseases like Diabetes mellitus. The potential of Coagulin L (a constituent of Withania coagulans) as dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated by molecular modelling study. It was observed that amino acid residues such as Glu205, Glu206, Tyr 547, His 740, and Try662 interacts with Coagulin L and Saxagliptin (a known DPP-4 inhibitor). Other nonbonded interactions of Coagulin L and Saxagliptin with DPP-4 binding residues were also found similar. The docking energy of Coagulin L was found to be ?7.69 Kcal/mol whereas ?8.44 kcal/mol was recorded for Saxagliptin. MD simulation study revealed stable binding throughout 100 ns simulation. RMSD plot of the complex was stabilized in 43 ns and remained stable during entire simulation(100 ns). RMSF plot of DPP-4 Coagulin L interaction showed major fluctuations at residue 246 and 766, however, Arg 125, Glu 205, Ser 209 and His 740 showed no major perturbations. Principal Component Analysis showed that important dynamics of the protein remain unchanged during entire simulation since the non-polar, van der waals, ionic interaction and solvation energy, altogether play important role in the complex stability. The molecular modelling study of DPP-4 with Coagulin L was an effort to establish correlation with traditional practices of Withania coagulans as antidiabetic agent in Indian subcontinent. Communicated by Ramaswamy H. Sarma. � 2020 Informa UK Limited, trading as Taylor & Francis Group.Publication Molecular modelling study to discover novel JAK2 signaling pathway inhibitor(Taylor and Francis Ltd., 2023) Singh, Amit; Mishra, AbhaThe JAK2/STAT signaling cascades facilitates receptor signals which is responsible for cell growth, survival and homeostasis. Ligand binding to JAKs causes phosphorylation other proteins known as STATs, which translocate to the nucleus and regulate transcription of several important proteins. Growth hormone, prolactin and ?-interferon known agonists of JAK STAT receptors, signal to the nucleus by a more direct manner than the receptor tyrosine kinases. Mutations in JAKs may be responsible for immunodeficiency and myeloproliferative disorders because of its important role in cytokine signaling and making the pathway a therapeutic target for various disease. The present study screened Zinc database to find novel JAK2 inhibitors using virtual high throughput screening techniques. Selection of compound for further study was on the basis of docking score, free energy and binding pattern of the compound. Molecular simulation and MM/GBSA free energy was evaluated for the binding interactions and the stability of docked conformations. Several parameters which determine protein ligand interaction like RMSD, RMSF, Rg and binding pattern were observed. Hydrogen bonds (Glu 930, 932 and Asp 994) after 150 ns simulation were observed between identified compound INC000096136346 and it was similar to known inhibitor ruxolitinib. MM/GBSA free energy was comparable to known inhibitor ruxolitinib. ZINC000096136346 qualify Lipinski�s rule of five, rule of three, WDI like rule and there is one violation in lead like rule. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.Publication Novel allosteric inhibitor to target drug resistance in EGFR mutant: molecular modelling and free energy approach(Taylor and Francis Ltd., 2022) Singh, Amit; Saini, Ravi; Mishra, AbhaAnticancer therapy targets Tyrosine kinase (TK) to inhibit signal transduction pathway that regulate various physiological and biochemical processes. Mutation in and around the catalytic domain may lead to conformational changes and activity. The first identified mutation leading to resistance against tyrosine kinase inhibitor (TKI) was observed when Thr at 790 replaced to Met in Epidermal Growth Factor Receptor (EGFR). Third generation EGFR-TKIs bind irreversibly to the Cysteine 797, (ATP-binding pocket). Mutation of Cys 797 to Ser residue (EGFRC797S) causes resistance to third generation TKI. The present study explores allosteric inhibitor of EGFRT790M+C797S mutant TK by molecular modelling techniques using 3,92,945 compounds of Zinc database. Molecular docking study revealed that ZINC000072404720 have similar binding pattern and MM/GBSA free energy as known allosteric inhibitor EAI045. RMSD of EGFRT790M+C797S bound to EAI045 and ZINC000072404720 were quite similar and in acceptable range. Hydrogen bonds after 150ns simulation was observed between Lys 745 and Asp 855 with EAI045 and novel inhibitor showed hydrogen bonding with Lys 745, Leu 788, Thr 854, Asp 855, Phe 856. MM/GBSA free energy was better (-84.09 Kcal/mol) known inhibitor EAI045b (-65.95 Kcal/mol). ZINC000072404720 fulfils drug likeliness property and did not violate Lipinski�s rule of five. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
