Molecular Docking and Interactions of Pueraria Tuberosa with Vascular Endothelial Growth Factor Receptors.
01 Jul 2015-Indian Journal of Pharmaceutical Sciences (Indian J Pharm Sci)-Vol. 77, Iss: 4, pp 439-445
TL;DR: The interaction pattern of the puerarone and tuberostan may provide a hint for a novel drug design for vascular endothelial growth factor tyrosine kinase receptors with better specificity to treat angiogenic disorders.
Abstract: Pueraria tuberosa is known for its therapeutic potentials in cardiovascular disorders, but its effect in angiogenesis has not been studied so far. In this study, a computational approach has been applied to elucidate the role of the phytochemicals in inhibition of angiogenesis through modulation of vascular endothelial growth factor receptors: Vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2, major factors responsible for angiogenesis. Metabolite structures retrieved from PubChem and KNApSAcK - 3D databases, were docked using AutoDock4.2 tool. Hydrogen bond and molecular docking, absorption, distribution, metabolism and excretion and toxicity predictions were carried out using UCSF Chimera, LigPlot(+) and PreADMET server, respectively. From the docking analysis, it was observed that puerarone and tuberostan had significant binding affinity for the intracellular kinase domain of vascular endothelial growth factor receptors-1 and vascular endothelial growth factor receptor-2 respectively. It is important to mention that both the phytochemicals shared similar interaction profile as that of standard inhibitors of vascular endothelial growth factor receptors. Also, both puerarone and tuberostan interacted with Lys861/Lys868 (adenosine 5'-triphosphate binding site of vascular endothelial growth factor receptors-1/vascular endothelial growth factor receptors-2), thus providing a clue that they may enforce their inhibitory effect by blocking the adenosine 5'-triphosphate binding domain of vascular endothelial growth factor receptors. Moreover, these molecules exhibited good drug-likeness, absorption, distribution, metabolism and excretion properties without any carcinogenic and toxic effects. The interaction pattern of the puerarone and tuberostan may provide a hint for a novel drug design for vascular endothelial growth factor tyrosine kinase receptors with better specificity to treat angiogenic disorders.
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TL;DR: Through molecular docking, this study found Puerarone and Robinin to be the most potential phytochemicals of PTWE for DPP-IV inhibition, and provides the novel active components that contribute to the D PP-IV inhibitory property ofPTWE.
Abstract: We had earlier reported that the extract of Pueraria tuberosa significantly inhibits DPP-IV enzyme, resulting in glucose tolerance response in rats. In this study, we have explored the active phytochemicals responsible for this potential. The results have been validated in both fasting and postprandial states in the plasma of normal rats and also in fasting blood and intestinal homogenates of diabetic models. Pueraria tuberosa water extract (PTWE) was administered to normal Charles Foster rats for 35 days and to diabetic model (65 mg/kg bw) for 10 days. After treatments, oral glucose tolerance test (OGTT) and insulin was done for 90 min, and the changes in the levels of GLP-1, GIP, and DPP-IV activities were monitored in fasting and postprandial states. In the case of the diabetic model, DPP-IV activity was measured in intestinal homogenate and basal insulin in plasma. The components of PTWE were analyzed via HPLC-MS based on their chemical formula, molecular mass, and retention time. Using the molecular docking study, we have selected the top five components having strong binding energy with DPP-IV. The increase in secretion of GLP-1 and GIP was significantly higher in the postprandial state when compared to fasting condition. GLP-1 plasma concentration increased by 5.8 and 2.9 folds and GIP increased by 8.7 and 2.4 folds in PTWE and control rats, respectively. In contrast, the postprandial decrease in DPP-IV specific activities was recorded at 2.3 and 1.4 folds. The response in OGTT and insulin was also consistent with these changes. In comparison to diabetic controls, PTWE-administered rats showed decreased DPP-IV activity in the intestine, leading to enhanced basal insulin concentration. Through molecular docking, we found Puerarone and Robinin to be the most potential phytochemicals of PTWE for DPP-IV inhibition. Binding energy (kcal/mol) and dissociation constant (pM) of Robinin with DPP-IV protein were found to be 7.543 and 2,957,383.75, respectively. For Puerarone, it was 7.376 and 3,920,309, respectively. Thus, this study provides the novel active components that contribute to the DPP-IV inhibitory property of PTWE.
28 citations
Cites background from "Molecular Docking and Interactions ..."
...PT tubers possess many components such as daidzin, puerarin, puerarone, genistein, puetuberosanol, tuberostan, tuberosin, and puerarin 4′,6′-diacetate [32]....
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TL;DR: The MD simulation results suggest that compound-17 binds strongly with RdRp of SARS-CoV-2 and has the potential to develop as a new antiviral against COVID-19 and can be one of the potential candidates for the treatment of CO VID-19.
Abstract: Antiviral drug therapy against SARS-CoV-2 is not yet established and posing a serious global health issue. Remdesivir is the first antiviral compound approved by the US FDA for the SARS-CoV-2 treatment for emergency use, targeting RNA-dependent RNA polymerase (RdRp) enzyme. In this work, we have examined the action of remdesivir and other two ligands screened from the library of nucleotide analogues using docking and molecular dynamics (MD) simulation studies. The MD simulations have been performed for all the ligand-bound RdRp complexes for the 30 ns time scale. This is one of the earlier reports to perform the MD simulations studies using the SARS-CoV-2 RdRp crystal structure (PDB ID 7BTF). The MD trajectories were analyzed and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were performed to calculate the binding free energy. The binding energy data reveal that compound-17 (-59.6 kcal/mol) binds more strongly as compared to compound-8 (-46.3 kcal/mol) and remdesivir (-29.7 kcal/mol) with RdRp. The detailed analysis of trajectories shows that the remdesivir binds in the catalytic site and forms a hydrogen bond with the catalytic residues from 0 to 0.46 ns. Compound-8 binds in the catalytic site but does not form direct hydrogen bonds with catalytic residues. Compound-17 showed the formation of hydrogen bonds with catalytic residues throughout the simulation process. The MD simulation results such as hydrogen bonding, the center of mass distance analysis, snapshots at a different time interval, and binding energy suggest that compound-17 binds strongly with RdRp of SARS-CoV-2 and has the potential to develop as a new antiviral against COVID-19. Further, the frontier molecular orbital analysis and molecular electrostatic potential (MESP) iso-surface analysis using DFT calculations shed light on the superior binding of compound-17 with RdRp compared to remdesivir and compound-8. The computed as well as the experimentally reported pharmacokinetics and toxicity parameters of compound-17 is encouraging and therefore can be one of the potential candidates for the treatment of COVID-19.
27 citations
TL;DR: In addition to previously studied DPPIV inhibitor, PTY-2 also acts as incretin receptors agonist and protects against STZ-induced diabetes by down regulating β cells apoptosis.
21 citations
Cites background from "Molecular Docking and Interactions ..."
...tuberosa tubers are rich in steroid, triterpenoid, glycoside, carbohydrate, alkaloids, flavanoid, tannin, protein, and amino acids [2,9] such as daidzin, puerarin, puerarone, genistein, puetuberosanol, tuberostan, tuberosin, and puerarin 4′,6′-diacetate [10]....
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Journal Article•
TL;DR: It has been found that 8-c-ascorbyl-(-)-epigallocatechin, rutin and orientin could be the putative molecules for amelioration of post-prandial hyperglycaemia whereas 8- c-asc or byl epigallocatedchin 3-o-gallate and schaftoside could be used to reduce fat absorption in obese persons.
Abstract: Black tea is one of the most widely consumed beverages in the world and traditionally known for its antidiabetic and antiobese property. However, the underlying mechanisms of these properties are not studied widely. In this work, we hypothesize that the reason could be because of the inhibition of gut enzymes by the tea derived phytochemicals. Molecular docking was used to explore the efficacy of tea components to inhibit the key enzymes related with Type II diabetes and obesity; α-glucosidase, α-amylase and lipase. Autodock4.2 molecular docking software that applies Lamarckian Genetic Algorithm was used. The ligand structures were retrieved from PubChem and KNApSAcK-3D database. PreADMET web server was used for Toxicity and ADME predictions. Based on this analysis, it has been found that 8-c-ascorbyl-(-)-epigallocatechin, rutin and orientin could be the putative molecules for amelioration of post-prandial hyperglycaemia whereas 8-c-ascorbyl-(-)-epigallocatechin, 8-c-ascorbyl epigallocatechin 3-o-gallate and schaftoside could be used to reduce fat absorption in obese persons. It can be concluded that these phytochemicals or their derivatives can be used for further in-vitro and in-vivo studies to design valuable drugs.
18 citations
Cites result from "Molecular Docking and Interactions ..."
...The softwares and methodology used in the study is similar to our earlier published works (Asthana et al., 2014; Asthana et al., 2015)....
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TL;DR: The results showed that PTY-2 favorably changed all the expressions via anti-oxidant, anti-apoptotic,Anti-hypoxic and anti-inflammatory pathways, making itself as a protective agent against streptozotocin induced islet stress in rats.
Abstract: The earlier assessment of Pueraria tuberosa (PT) has shown anti-diabetic effects through enhancing incretin action and DPP-IV (Dipeptidyl peptidase-IV) inhibition. The aim of this work was to further explore the protective role of aqueous extract of Pueraria tuberosa tuber (PTY-2) against streptozotocin (STZ) induced islet stress in rats. Diabetes was induced by STZ (65 mg/kg body weight) in charles foster male rats. After 60 days of STZ administration, animals with blood glucose levels > 200 g/dL were considered as diabetic. All the rats were later divided into three groups: Group-1 (STZ untreated normal rats), Group-2 (Diabetic control), and Group-3 (PTY-2 [50 mg/100 g bw treatment for next 10 days to diabetic rats). The rats were then sacrificed after the 10th day of treatment accordingly. STZ treatment led to an increase in expression of Matrix metalloproteinases-9 (MMP-9), Tumour necrosis factor-α (Tnf-α), Hypoxia inducible factor-α (HIF-1α), Vascular endothelial growth factor (VEGF), Interleukin-6 (IL-6), Protein kinase C-e (PKC-e), Nuclear factor kappa-light-chain-enhancer of activated B-cells (NFkB), and Caspase-3. Reverse Transcriptase-PCR (RT-PCR), Immunohistochemistry and Western-Blot analysis showed an increase in the expressions of Superoxide Dismutase (SOD) and Nephrin, and a decrease in the expressions of NFkB, PKC-e, TNF-α, MMP-9, HIF-1α, VEGF, Caspase-3 and IL-6 after 10 days of PTY-2 treatment. The results showed that PTY-2 favorably changed all the expressions via anti-oxidant, anti-apoptotic, anti-hypoxic and anti-inflammatory pathways, making itself as a protective agent against STZ induced islet stress. Further evaluation of PTY-2 might be helpful in establishing its role in the management of diabetes mellitus.
8 citations
References
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TL;DR: It could be suggested that tuberosin, is one of the active principles of Pueraria tuberose, which directly scavenges various species of Free radicals (FRs) and also inhibits LPS induced inflammatory changes in macrophages.
Abstract: Antioxidant activity of Pueraria tuberose DC, (PT) Leguminosae (Fabaceae) has already been reported by us and here an active compound has been isolated and its action on expression of iNOS protein has been explored by using LPS induced changes in attached rat peritoneal macrophage cell culture. The pure compound was isolated by column chromatography and its structure was characterized by spectral studies, which was identified as tuberosin (5 hydroxy 3,4,7,3',4' pentamethoxy flavone). Its antioxidant capacity was determined and compared with alcoholic extract as EC50 value for scavenging potential towards pre-generated monocation ABTS* radical, superoxide radicals, hydroxyl radicals, metal chelation property and on lipid peroxidation. Further, rat peritoneal macrophages were isolated, cultured and the attached macrophages were exposed to lipopolysaccharide (LPS) with different concentrations of tuberosin (pretreatment for 30 min). After 17 h the released NO content, in culture supernatant, was indirectly estimated as accumulated nitrite by Griess reagent. To understand the mechanism of action, the extent of expression of inducible nitric oxide synthase genes, the iNOS protein was assessed in macrophage lysate by using its antibody on western blot analysis. Tuberosin significantly scavenged all the species of FRs, described above and it also inhibited the LPS induced release of NO and amount of iNOS protein in macrophages. All the changes were significant and concentration dependent. Thus it could be suggested that tuberosin, is one of the active principles of Pueraria tuberose, which directly scavenges various species of Free radicals (FRs) and also inhibits LPS induced inflammatory changes in macrophages.
46 citations
Additional excerpts
...C00010049 Tuberostan Pueraria tuberosa (vidarikanda) [27]...
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29 Jul 2013
TL;DR: The results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential interaction with VEGF.
Abstract: Angiogenesis, or new blood vessel formation from existing one, plays both beneficial and detrimental roles in living organisms in different aspects. Vascular endothelial growth factor (VEGF), a signal protein, well established as key regulator of vasculogenesis and angiogenesis. VEGF ensures oxygen supply to the tissues when blood supply is not adequate, or tissue environment is in hypoxic condition. Limited expression of VEGF is necessary, but if it is over expressed, then it can lead to serious disease like cancer. Cancers that have ability to express VEGF are more efficient to grow and metastasize because solid cancers cannot grow larger than a limited size without adequate blood and oxygen supply. Anti-VEGF drugs are already available in the market to control angiogenesis, but they are often associated with severe side-effects like fetal bleeding and proteinuria in the large number of patients. To avoid such side-effects, new insight is required to find potential compounds as anti-VEGF from natural sources. In the present investigation, molecular docking studies were carried out to find the potentiality of Withaferin A, a key metabolite of Withania somnifera, as an inhibitor of VEGF. Molecular Docking studies were performed in DockingServer and SwissDock. Bevacizumab, a commercial anti-VEGF drug, was used as reference to compare the activity of Withaferin A. X-ray crystallographic structure of VEGF, was retrieved from Protein Data Bank (PDB), and used as drug target protein. Structure of Withaferin A and Bevacizumab was obtained from PubChem and ZINC databases. Molecular visualization was performed using UCSF Chimera. Withaferin A showed favorable binding with VEGF with low binding energy in comparison to Bevacizumab. Molecular Docking studies also revealed potential protein-ligand interactions for both Withaferin A and Bevacizumab. Conclusively our results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential interaction with VEGF. This scientific hypothesis might provide a better insight to control angiogenesis as well as to control solid cancer growth and metastasis.
44 citations
"Molecular Docking and Interactions ..." refers background in this paper
...Recently, a number of plant derived natural compounds or phytochemicals have been reported possesing a potential antiangiogenic activity[6,7]....
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TL;DR: The antiangiogenic activity of plants used in traditional Korean medicine implicates their possible application for diseases where inhibition of blood vessel formation is desired, for example, cancer, macular degeneration, diabetic retinopathy and others.
Abstract: Aim. In the present study, we investigated the antiangiogenic properties of 59 plants used in traditional Korean medicine. Selected phytochemicals were investigated in more detail for their modes of action. Methods. A modified chicken-chorioallantoic-membrane (CAM) assay using quail eggs was applied to test for antiangiogenic effects of plant extracts. A molecular docking in silico approached the binding of plant constituents to the vascular endothelial growth factor receptors 1 and 2 (VEGFR1, VEGFR2). Microarray-based mRNA expression profiling was employed to correlate the 50% inhibition concentrations (IC50) of a panel of 60 NCI cell lines to these phytochemicals. Results. Extracts from Acer mono leaves, Reynoutria sachalniensis fruits, Cinnamomum japonicum stems, Eurya japonica leaves, Adenophora racemosa whole plant, Caryopteris incana leaves-stems, and Schisandra chinensis stems inhibited angiogenesis more than 50% in quail eggs. Selected phytochemicals from Korean plants were analyzed in more detail using microarray-based mRNA expression profiles and molecular docking to VEGFR1 and VEGFR2. These results indicate multifactorial modes of action of these natural products. Conclusion. The antiangiogenic activity of plants used in traditional Korean medicine implicates their possible application for diseases where inhibition of blood vessel formation is desired, for example, cancer, macular degeneration, diabetic retinopathy and others.
30 citations
"Molecular Docking and Interactions ..." refers background in this paper
...Vascular endothelial growth factor receptor 1 VEGFR1 3HNG Homo Sapiens [24]...
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...The above TABLE 1: TARGETS TO CHECK THE EFFECT ON ANGIOGENESIS Proteins Notations PDB ID Organism References Vascular endothelial growth factor receptor 1 VEGFR1 3HNG Homo Sapiens [24] mentioned binding energies along with the interaction profile (hydrogen bonds and hydrophobic interactions) provide an important indication for the affinity and stability of ligand with the protein....
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TL;DR: 7-Methoxy-6-(7-methoxychrornan-3-yl)-2,2-dimethylchroman (X) has been synthesized and shown to be identical with a degradation product from tuberosin.
Abstract: Tuberosin, a new pterocarpan isolated from Pueraria tuberosa DC. has been identified as 6a,13a-dihydro-10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g′]bis[1]benzopyran-3,6a-diol (III). 7-Methoxy-6-(7-methoxychrornan-3-yl)-2,2-dimethylchroman (X) has been synthesized and shown to be identical with a degradation product from tuberosin.
28 citations
"Molecular Docking and Interactions ..." refers background in this paper
...Tubers of Pueraria tuberosa are rich in daidzin, puerarin, puerarone, genistein, puetuberosanol, tuberostan, tuberosin, and puerarin 4’,6’-diacetate[15-17]....
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TL;DR: Treatment with anti-angiogenic compounds might be advantageous over conventional chemotherapy due to the fact that those compounds mainly act on endothelial cells, which are genetically more stable and homogenous compared to tumor cells and they show lower susceptibility to acquired drug resistance (ADR).
Abstract: Cancer is a major cause of death worldwide and angiogenesis is critical in cancer progression. Development of new blood vessels and nutrition of tumor cells are heavily dependent on angiogenesis. Thus, angiogenesis inhibition might be a promising approach for anticancer therapy. Anti-angiogenic small molecule and phytochemicals as a cancer treatment approach are focused in these main points; modes of action, adverse effects, mechanisms of resistance and new developments. Treatment with anti-angiogenic compounds might be advantageous over conventional chemotherapy due to the fact that those compounds mainly act on endothelial cells, which are genetically more stable and homogenous compared to tumor cells and they show lower susceptibility to acquired drug resistance (ADR). Targeting the VEGF (vascular endothelial growth factor) signalling pathway with synthetic small molecules inhibiting Receptor Tyrosine Kinases (RTKs) in addition to antagonizing VEGF might be a promising approach. Moreover, beneficial effect of phytochemicals were proven on cancer-related pathways especially concerning anti-angiogenesis. Plant phenolics being an important category of prominent phytochemicals affect different pathways of angiogenesis. Green tea polyphenols (epigallocatechin gallate) and soy bean isoflavones (genistein) are two examples involving an anti-angiogenic effect.
22 citations
"Molecular Docking and Interactions ..." refers background in this paper
...Recently, a number of plant derived natural compounds or phytochemicals have been reported possesing a potential antiangiogenic activity[6,7]....
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