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Molecular docking studies of phytochemicals from Phyllanthus niruri against Hepatitis B DNA Polymerase.

ABSTRACT: Hepatitis B virus (HBV) infection is the leading cause for liver disorders and can lead to hepatocellular carcinoma, cirrhosis and liver damage which in turn can cause death of patients. HBV DNA Polymerase is essential for HBV replication in the host and hence is used as one of the most potent pharmacological target for the inhibition of HBV. Chronic hepatitis B is currently treated with nucleotide analogues that suppress viral reverse transcriptase activity and most of them are reported to have viral resistance. Therefore, it is of interest to model HBV DNA polymerase to dock known phytochemicals. The present study focuses on homology modeling and molecular docking analysis of phytocompounds from the traditional antidote Phyllanthus niruri and other nucleoside analogues against HBV DNA Polymerase using the software Discovery studio 4.0. 3D structure of HBV DNA Polymerase was predicted based on previously reported alignment. Docking studies revealed that a few phytochemicals from Phyllanthus niruri had good interactions with HBV DNA Polymerase. These compounds had acceptable binding properties for further in vitro validation. Thus the study puts forth experimental validation for traditional antidote and these phytocompounds could be further promoted as potential lead molecule.

SUBMITTER: Mohan M

PROVIDER: S-EPMC4620619 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Molecular docking studies of phytochemicals from Phyllanthus niruri against Hepatitis B DNA Polymerase.

Mohan Mekha M James Priyanka P Valsalan Ravisankar R Nazeem Puthiyaveetil Abdulla PA

Bioinformation 20150930 9

Hepatitis B virus (HBV) infection is the leading cause for liver disorders and can lead to hepatocellular carcinoma, cirrhosis and liver damage which in turn can cause death of patients. HBV DNA Polymerase is essential for HBV replication in the host and hence is used as one of the most potent pharmacological target for the inhibition of HBV. Chronic hepatitis B is currently treated with nucleotide analogues that suppress viral reverse transcriptase activity and most of them are reported to have ...[more]

PMID: 26527851

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Project description:Doxorubicin (DOX) is a cornerstone chemotherapeutic agent for the treatment of several malignancies such as breast cancer; however, its activity is ameliorated by the development of a resistant phenotype. Phyllanthus species have been studied previously for their potential anticancer properties. The current work is aimed to study the potential cytotoxicity and chemomodulatory effects of hypophyllanthin (PN4) and phyllanthin (PN5) isolated from Phyllanthus niruri to DOX against the adriamycin multidrug-resistant breast cancer cells (MCF-7ADR) and elucidate their mechanism of action. The major compounds of the active methylene chloride fraction were isolated and assessed for their potential cytotoxicity and chemomodulatory effects on DOX against naïve (MCF-7) and resistant breast (MCF-7ADR) cancer cells. The mechanism of action of both compounds in terms of their impacts on programmed/non-programmed cell death (apoptosis and autophagy/necrosis), cell cycle progression/arrest, and tumor cell migration/invasion was investigated. Both compounds PN4 and PN5 showed a moderate but similar potency against MCF-7 as well as MCF-7ADR and significantly synergized DOX-induced anticancer properties against MCF-7ADR. The chemomodulatory effect of both compounds to DOX was found to be via potentiating DOX-induced cell cycle interference and apoptosis induction. It was found that PN4 and PN5 blocked the apoptosis-escape autophagy pathway in MCF-7ADR. On the molecular level, both compounds interfered with SIRT1 expression and consequently suppressed Akt phosphorylation, and PN5 blocked apoptosis escape. Furthermore, PN4 and PN5 showed promising antimigratory and anti-invasive effects against MCF-7ADR, as confirmed by suppression of N-cadherin/β-catenin expression. In conclusion, for the first time, hypophyllanthin and phyllanthin isolated from P. niruri showed promising chemomodulatory effects to the DOX-induced chemotherapeutic activity against MCF-7ADR. Both compounds significantly synergized DOX-induced anticancer properties against MCF-7ADR. This enhanced activity was explained by further promoting DOX-induced apoptosis and suppressing the apoptosis-escape autophagy feature of the resistant breast cancer cells. Both compounds (hypophyllanthin and phyllanthin) interfered with the SIRT1/Akt pathway and suppressed the N-cadherin/β-catenin axis, confirming the observed antiproliferative, cytotoxic, and anti-invasive effects of hypophyllanthin and phyllanthin.

Project description:Phyllanthus niruri L. is a widespread tropical plant which is used in Ayurvedic system for liver and kidney ailments. The present study aims at specifying the most active hepatoprotective extract of P. niruri and applying a bio-guided protocol to identify the active compounds responsible for this effect. P. niruri aerial parts were extracted separately with water, 50%, 70% and 80% ethanol. The cytoprotective activity of the extracts was evaluated against CCl4-induced hepatotoxicity in clone-9 and Hepg2 cells. Bioassay-guided fractionation of the aqueous extract (AE) was accomplished for the isolation of the active compounds. Antioxidant activity was assessed using DPPH (1, 1-diphenyl-2-picrylhydrazyl) radical scavenging method and ferric reducing antioxidant power (FRAP). The in vivo hepatoprotective activity of AE was evaluated in CCl4-induced hepatotoxicity in rats at different doses after determination of its LD50. Pretreatment of clone-9 and Hepg2 with different concentrations of AE (1, 0.1, 0.01 mg/ml) had significantly reduced the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) against CCl4 injures, and restored the activity of the natural antioxidants; glutathione (GSH) and superoxide dismutase (SOD) towards normalization. Fractionation of AE gave four fractions (I-IV). Fractions I, II, and IV showed a significant in vitro hepatoprotective activity. Purification of I, II and IV yielded seven compounds; corilagin C1, isocorilagin C2, brevifolin C3, quercetin C4, kaempferol rhamnoside C5, gallic acid C6, and brevifolin carboxylic acid C7. Compounds C1, C2, C5, and C7 showed the highest (p< 0.001) hepatoprotective potency, while C3, C4, and C6 exhibited a moderate (p< 0.001) activity. The AE exhibited strong antioxidant DPPH (IC50 11.6 ± 2 μg/ml) and FRAP (79.352 ± 2.88 mM Ferrous equivalents) activity. In vivo administration of AE in rats (25, 50, 100 and 200 mg/kg) caused normalization of AST, ALT, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total cholesterol (TC), triglycyrides (TG), total bilirubin (TB), glucose, total proteins (TP), urea and creatinine levels which were elevated by CCl4. AE also decreased TNF-α, NF-KB, IL-6, IL-8, IL10 and COX-2 expression, and significantly antagonizes the effect of CCl4 on the antioxidant enzymes SOD, catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GSP). The histopathological study also supported the hepatoprotective effect of AE. P. niruri isolates exhibited a potent hepatoprotective activity against CCl4-induced hepatotoxicity in clone-9 and Hepg2 cell lines through reduction of lipid peroxidation and maintaining glutathione in its reduced form. This is attributable to their phenolic nature and hence antioxidative potential.

Project description:The SARS-Cov-2 virus, which is evolving continuously and causing adverse effects throughout the world, needs an effective drug molecule for its treatment. There are several receptors of SARS Cov-2 which are targeted for its inhibition by many lead molecules both in-vitro and in-vivo. Papain like Protease (PLpro) is one of the two SARS-Cov-2 proteases that can be used as a drug target for SARS Cov-2. It is a coronavirus enzyme that plays a role in the cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex and disruption of host responses. PLpro has also been linked to the cleavage of proteinaceous post translational modifications on host proteins as a means of evading antiviral immune responses. Structure-based drug discovery can be one of the effective methods to screen for various molecules against the target receptors. In this study, PLpro of SARS CoV-2 was chosen as the target for docking. Forty phytochemicals from various plant sources and four synthetic drugs have been screened for their inhibitory potential against PLpro using AutoDock Vina. Phytochemicals such as Tinosponone, Rhoifolin, Rosmanol, Berberin, Nimbin and two other existing drugs Elbasvir and Declatasvir showed higher inhibitory potential in terms of higher binding affinities. ADME and toxicity analysis were also performed to predict the pharmacokinetics and drug likeliness properties. It was concluded from the study that Tinosponone possesss potential inhibitor property of papain-like proteases (PLpro) of SARS CoV-2. Tinosponone from the plant Tinospora cordifolia had a binding affinity of - 9.3 kcal/mol and obeyed the Lipinski rules, making it an effective lead molecule for treating SARS CoV-2. Molecular Dynamics simulation of Tinosponone with PLpro has proved the stability and validity of the binding with RMSD value in range of 0.2 nm when it was run for 50 ns using GROMACS. Therefore, Tinosponone could be considered as a potential inhibitor of PLpro of SARS CoV-2.

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Molecular docking studies of phytochemicals from Phyllanthus niruri against Hepatitis B DNA Polymerase.

Publications

Molecular docking studies of phytochemicals from Phyllanthus niruri against Hepatitis B DNA Polymerase.

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