Browsing by Author "Sharad Verma"

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Complex disruption effect of natural polyphenols on Bcl-2-Bax: Molecular dynamics simulation and essential dynamics study
(Taylor and Francis Ltd., 2015) Sharad Verma; Amit Singh; Abha Mishra
Apoptosis (programmed cell death) is a process by which cells died after completing physiological function or after a severe genetic damage. Apoptosis is mainly regulated by the Bcl-2 family of proteins. Anti apoptotic protein Bcl-2 prevents the Bax activation/oligomerization to form heterodimer which is responsible for release of the cytochrome c from mitochondria to the cytosol in response to death signal. Quercetin and taxifolin (natural polyphenols) efficiently bound to hydrophobic groove of Bcl-2 and altered the structure by inducing conformational changes. Taxifolin was found more efficient when compared to quercetin in terms of interaction energy and collapse of hydrophobic groove. Taxifolin and quercetin were found to dissociate the Bcl-2-Bax complex during 12 ns MD simulation. The effect of taxifolin and quercetin was, further validated by the MD simulation of ligand-unbound Bcl-2-Bax which showed stability during the simulation. Obatoclax (an inhibitor of Bcl-2) had no significant dissociation effect on Bcl-2-Bax during simulation which favored the previous experimental results and disruption effect of taxifolin and quercetin. © 2014 Taylor & Francis.
Dual inhibition of chaperoning process by taxifolin: Molecular dynamics simulation study
(2012) Sharad Verma; Amit Singh; Abha Mishra
Hsp90 (heat shock protein 90), a molecular chaperone, stabilizes more than 200 mutated and over expressed oncogenic proteins in cancer development. Cdc37 (cell division cycle protein 37), a co-chaperone of Hsp90, has been found to facilitate the maturation of protein kinases by acting as an adaptor and load these kinases onto the Hsp90 complex. Taxifolin (a natural phytochemical) was found to bind at ATP-binding site of Hsp90 and stabilized the inactive "open" or "lid-up" conformation as evidenced by molecular dynamic simulation. Furthermore, taxifolin was found to bind to interface of Hsp90 and Cdc37 complex and disrupt the interaction of residues of both proteins which were essential for the formation of active super-chaperone complex. Thus, taxifolin was found to act as an inhibitor of chaperoning process and may play a potential role in the cancer chemotherapeutics. © 2012 Elsevier Inc.
Gallic acid: Molecular rival of cancer
(2013) Sharad Verma; Amit Singh; Abha Mishra
Gallic acid, a predominant polyphenol, has been shown to inhibit carcinogenesis in animal models and in vitro cancerous cell lines. The inhibitory effect of gallic acid on cancer cell growth is mediated via the modulation of genes which encodes for cell cycle, metastasis, angiogenesis and apoptosis. Gallic acid inhibits activation of NF-κB and Akt signaling pathways along with the activity of COX, ribonucleotide reductase and GSH. Moreover, gallic acid activates ATM kinase signaling pathways to prevent the processes of carcinogenesis. The data so far available, both from in vivo and in vitro studies, indicate that this dietary polyphenol could be promising agent in the field of cancer chemoprevention. © 2013 Elsevier B.V..
Molecular construction of NADH-cytochrome b5 reductase inhibition by flavonoids and chemical basis of difference in inhibition potential: Molecular dynamics simulation study
(2012) Sharad Verma; Amit Singh; Abha Mishra
NADH-cytochrome b5 reductase, a flavoprotein, plays a central role in many diverse metabolic reactions. NADH-cytochrome b5 reductase has been shown to be responsible for the generation of free radicals from heterocyclic amines. Flavonoids compounds share remarkable similarity in structure but showed differences in their cytochrome b5 reductase inhibition pattern. Our molecular dynamics simulation studies revealed that the difference in substitution at C3 position of ring C may lead to difference in interaction with enzyme. Absence of hydroxyl group substitution at C3 in luteolin facilitates the strong cation-p interaction between Lys185 and ring A, and C and p-p between Phe92 and ring A, and C along with h-bonding between Lys185 and oxo group. Ring B of luteolin showed strong π-π interaction with FAD. These interactions were found absent in quercetin and taxifolin. These results suggest that absence of hydroxyl group substitution at C3 increases the potency of flavonoid inhibitors for cytochrome b5 reductase.
Molecular dynamics investigation on the inhibition of MDM2-p53 interaction by polyphenols
(Wiley-VCH Verlag, 2013) Sharad Verma; Amit Singh; Abha Mishra
Inhibition of the MDM2-p53 interaction has become a new therapeutic strategy to activate wild type p53 in tumors. Quercetin and taxifolin bind to p53 binding hydrophobic groove of MDM2, and alter the conformation of groove as evidenced by 65 ns molecular dynamics simulation. Quercetin showed hydrogen bonding with Gly 16, Ser 17, Phe 55 and Val 93 along with π-π interaction with His96 and π-σ with Phe 55. Taxifolin also showed similar interactions except π-σ interaction with Phe 55. Further, we found that binding of ligands lead to the dissociation of MDM2-p53 complex. These ligands form stable hydrophobic interactions with MDM2 which led to complete disruption of MDM2-p53 hydrophobic interactions and dissociation of p53 from the complex. It was found that the π-π stacking between Tyr 51 of MDM2 and ligands is the critical event in MDM2-p53 dissociation. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Molecular dynamics investigation on the poor sensitivity of A171T mutant NEDD8-activating enzyme (NAE) for MLN4924
(Adenine Press, 2014) Sharad Verma; Amit Singh; Abha Mishra
MLN4924 is an adenosine sulfamate analog that generates the inhibitory NEDD8-MLN4924 covalent complex. A single nucleotide transition that changes alanine 171 to threonine (A171T) of the NAE subunit UBA3 reduces the enzymes sensitivity for MLN4924. Our molecular dynamics simulation study revealed that A171T transition brought remarkable conformational changes in enzyme structure (open ATP binding pocket), which reduced the interaction between MLN4924 and ATP binding pocket while wild form completely covered the MLN4924. A total difference of -49.75 kJ/mol was noticed in interaction energy (electrostatic and van der Waals) during simulation between mutant and wild form with MLN4924. Superimposition of final 20 ns mutant structure with reference structure showed significant change in native binding position as compared to wild form. Results were found in coherence with the recently reported in vitro studies which states that A171T transition leads to change in ATP binding pocket structure. © 2013 © 2013 Taylor & Francis.
Quercetin and taxifolin completely break MDM2-p53 association: Molecular dynamics simulation study
(2013) Sharad Verma; Amit Singh; Abha Mishra
Inhibition of the MDM2-p53 interaction has been becomes a new therapeutic strategy to activate wild-type p53 in tumors. Molecular dynamics (MD) simulations were used to study the effects of quercetin and taxifolin on MDM2-p53 complex. We found that binding of ligands (quercetin and taxifolin) led to the dissociation of MDM2-p53 complex. Analyses of the hydrophobic contacts between the inhibitors and MDM2-p53 were performed, and the results suggested that these ligands form stable hydrophobic interactions with MDM2 which led to complete disruption of MDM2-p53 hydrophobic interactions and dissociation of p53 from the complex. Our study suggests that the pi-pi stacking between Tyr 51 of MDM2 and aromatic rings of ligands is the critical event in MDM2-p53 dissociation. © 2012 Springer Science+Business Media New York.
Taxifolin acts as type I inhibitor for VEGFR-2 kinase: Stability evaluation by molecular dynamic simulation
(2012) Sharad Verma; Amit Singh; Abha Mishra
The VEGFR-2 kinase specific intracellular signalling cascades leading to proliferation, migration, survival of endothelial cells and increased permeability of vessels which contributes to angiogenesis. ATP is essentially required by VEGFR-2 to perform phosphorylation of specific proteins and to maintain cascad e downstream. Taxifolin (plant polyphenol) inhibit the VEGFR-2 kinase by binding at ATP-bind ing pocket revealed by molecular docking study. Further, stability of VEGFR-2 kinase-taxifolin complex is validated by molecular dynamic simulation. RMSD analysis for 3800 ps confirmed the stability of complex. Furthermore, thermodynamic stability was evidenced by stable total energy, potential energy, and, temperature and pressure profile. After MD simulation taxifolin was found to stably interact with pocket residues Cys 917 and Lys 1053 along with water molecules. These results suggest that therapeutic inhibition of VEGFR-2 by taxifolin as a type I inhibitor may be a promising ways to retard signaling cascade of specific proteins which play crucial role in cancer proliferation and also in development of second generation type II inhibitors.
The effect of fulvic acid on pre- and postaggregation state of Aβ17-42: Molecular dynamics simulation studies
(2013) Sharad Verma; Amit Singh; Abha Mishra
Alzheimer's disease (AD), a neurodegenerative disorder, is directly related to the aggregation of Aβ peptides. These peptides can self-assemble from monomers to higher oligomeric or fibrillar structures in a highly ordered and efficient manner. This self-assembly process is accompanied by a structural transition of the aggregated proteins from their normal fold into a predominantly β-sheet secondary structure. 14 ns molecular dynamics simulation revealed that fulvic acid interrupted the dimer formation of Aβ17-42 peptide while in its absence Aβ17-42 dimer formation occurred at ∼ 12 ns. Additionally, fulvic acid disrupted the preformed Aβ17-42 trimer in a very short time interval (12 ns). These results may provide an insight in the drug design against Aβ17-42 peptide aggregation using fulvic acid as lead molecule against Aβ17-42 mediated cytotoxicity and neurodegeneration. © 2012 Elsevier B.V. All rights reserved.