Sharad Verma

Gallic acid: Molecular rival of cancer

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.

An in-silico strategy to explore neuroprotection by quercetin in cerebral ischemia: A novel hypothesis based on inhibition of matrix metalloproteinase (MMPs) and acid sensing ion channel 1a (ASIC1a)

Cerebral ischemia are caused by acute interruption of the brain arterial blood supply, typically by a thrombus or embolus, leading to neuronal insult and the remainder damage are caused by blood vessel rupture, leading to hemorrhage. Acidosis and matrix metalloproteinase activation are the central and prominent metabolic feature of ischemic brain. The combined inhibition of MMPs and ASIC1a channels can offer a new therapeutic approach in cerebral stroke management. Moreover, the combined inhibition of MMPs and ASIC1a with flavonoids remains unknown against neuroprotection in animal models of cerebral ischemia. Flavonoids are believed to act as health-promoting substances and some of them have antioxidant and anti-inflammatory properties. Therefore, the target of the present study was in-silico evaluation of the neuroprotective efficacy of quercetin in rat model of focal cerebral ischemia/reperfusion (I/R) injury and efforts were made to analyze its inhibitory effects on MMPs activation and ASIC1a channels mediated downstream survival/damage mechanisms. Thus on the basis of our in-silico studies we hypothesize that quercetin can be a neuroprotective agent in rat model of focal cerebral ischemia/reperfusion (I/R) injury due to its inhibitory effects on MMPs activation and ASIC1a channels mediated downstream survival/damage mechanisms.

Interaction between shrimp and white spot syndrome virus through PmRab7-VP28 complex: an insight using simulation and docking studies

White spot disease is a devastating disease of shrimp Penaeus monodon in which the shrimp receptor protein PmRab7 interacts with viral envelop protein VP28 to form PmRab7–VP28 complex, which causes initiation of the disease. The molecular mechanism implicated in the disease, the dynamic behavior of proteins as well as interaction between both the biological counterparts that crafts a micro-environment feasible for entry of virus into the shrimp is still unknown. In the present study, we applied molecular modeling (MM), molecular dynamics (MD) and docking to compute surface mapping of infective amino acid residues between interacting proteins. Our result showed that α-helix of PmRab7 (encompassing Ser74, Ile143, Thr184, Arg53, Asn144, Thr184, Arg53, Arg79) interacts with β-sheets of VP28 (containing Ser74, Ile143, Thr184, Arg53, Asn144, Thr184, Arg53, Arg79) and Arg69-Ser74, Val75-Ile143, Leu73-Ile143, Arg79-Asn144, Ala198-Ala182 bonds contributed in the formation of PmRab7–VP28 complex. Further studies on the amino acid residues and bonds may open new possibilities for preventing PmRab7–VP28 complex formation, thus reducing chances of WSD. The quantitative predictions provide a scope for experimental testing in future as well as endow with a straightforward evidence to comprehend cellular mechanisms underlying the disease.

The effect of fulvic acid on pre‐ and postaggregation state of Aβ17–42: Molecular dynamics simulation studies

Alzheimers 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. 14ns molecular dynamics simulation revealed that fulvic acid interrupted the dimer formation of Aβ(17-42) peptide while in its absence Aβ(17-42) dimer formation occurred at ~12ns. Additionally, fulvic acid disrupted the preformed Aβ(17-42) trimer in a very short time interval (12ns). These results may provide an insight in the drug design against Aβ(17-42) peptide aggregation using fulvic acid as lead molecule against Aβ(17-42) mediated cytotoxicity and neurodegeneration.

Quercetin and taxifolin completely break MDM2–p53 association: molecular dynamics simulation study

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.

Molecular Dynamics Investigation on the Inhibition of MDM2-p53 Interaction by Polyphenols

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.

Molecular construction of NADH-cytochrome b5 reductase inhibition by flavonoids and chemical basis of difference in inhibition potential: Molecular dynamics simulation study

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-π interaction between Lys185 and ring A, and C and π-π 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 poor sensitivity of A171T mutant NEDD8-activating enzyme (NAE) for MLN4924.

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 enzyme’s 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.

Regulation of wound strength by Ocimum sanctum: in silico and in vivo evidences

Wound healing is the process of repair that involves various cells and events follows injury to the skin and other soft tissues. The phases of normal wound healing include hemostasis, inflammation, proliferation and remodelling. Wound healing is directly related to interactions between cells and the components of the extracellular matrix (ECM). The ECM regulates the growth, proliferation, movement, and differentiation of the cells living within it. The ECM is composed of three groups of macromolecules: fibrous structural proteins, such as collagens and elastins that provide tensile strength and recoil; adhesive glycoproteins that connect the matrix elements to one another and to cells; and proteoglycans and hyaluronan that provide resilience and lubrication. Degradation of collagen and other ECM proteins is achieved by matrix metalloproteases, which consist of 23 distinct proteases in humans. 1 MMPs belong to four classes: the collagenases (MMP-1, -8 and -13), the gelatinases (MMP-2 and -9), the stromelysins (MMP-3, 10 and -11) and a heterogeneous group containing matrilysin (MMP-7), metallo-elastase (MMP-12), enamelysin (MMP-20), endometase (MMP-26) and epilysin (MMP-28). 2 The collagenases are rapidly inhibited by a family of specific tissue inhibitors of metalloproteinases (TIMP) thus preventing uncontrolled action of these proteases. These TIMPs are a group of ABSTRACT