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An in silico insight into molecular mechanism of hypoglycemic activity of Scoparic acid D, A diterpenoid from Scoparia dulcis L.
Abstract
Despite availability of preclinical report about antidiabetic activity of the molecule Scoparic Acid D isolated from Scoparia dulcis L. no clinical trial has reported to be initiated possibly because of the fact that molecular mechanism of hypoglycemic effect of the molecule was not explained properly. Considering the reported hypoglycemic potential of the molecule and looking at the alarming increase of diabetic population worldwide and particularly in India we wanted to explain the mode of action of the molecule using virtual screening technique. Target Fishing Technique was employed to find out suitable target for the molecule using PharmMapper server taking human targets as database. From the result, the topmost diabetes drug target was selected and Scoparic Acid D was docked with it using FlexX. Collecting from PubChem database, descriptors of 54 existing antidiabetic molecules were considered for developing QSAR model and activity of Scoparic Acid D was predicted with reference to the QSAR model developed. In a similar manner Docking score of two known commercially available human α-glucosidase enzyme inhibitor drugs, viz. Miglitol and Voglibose and their IC50 values were recorded and compared with that of Scoparic Acid D. The target fishing of Scoparic acid D revealed that it has a high potentiality to inhibit the human α-glucosidase enzyme, which is a target for Diabetes mellitus. Docking studies showed greater affinity of Scoparic Acid D towards the active site of human α-glucosidase with a docking score of -8.1675, which is better than that of existing 22 inhibitors out of 54 used in the study and is also comparable to that of two commercial drugs, which target human α-glucosidase enzyme. Predicted IC50 value of Scoparic Acid D was found to be 3.98μM which is better than that of the known human α-glucosidase enzyme inhibitor drug i.e., Voglibose (IC50: 5.6 μM). We, therefore, suggest that Scoparic Acid D may be a potent inhibitor of human α-glucosidase enzyme and thereby delaying digestion of starch and sucrose, flattening postprandial blood glucose excursions and mimicking the effects of dieting on hyperglycemhyperglycemia may be a potent drug for treating diabetes.
Ethno-botanical inspired isolation from plant Scoparia dulcis Linn. (Sweet Broomweed) yielded six compounds, coixol (1), glutinol (2), glutinone (3), friedelin (4), betulinic acid (5), and tetratriacontan-1-ol (6). There structures were identified using mass and 1D- and 2D-NMR spectroscopy techniques. Compounds 1-6 were evaluated for their insulin secretory activity on isolated mice islets and MIN-6 pancreatic β-cell line, and compounds 1 and 2 were found to be potent and mildly active, respectively. Compound 1 was further evaluated for insulin secretory activity on MIN-6 cells. Compound 1 was subjected to in vitro cytotoxicity assay against MIN-6, 3T3 cell lines, and islet cells, and in vivo acute toxicity test in mice that was found to be non-toxic. The insulin secretory activity of compounds 1 and 2 supported the ethno-botanic uses of S. dulcis as an anti-diabetic agent. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
Obesity and diabetes are diseases that emerge as serious health problems to our dayto-day life. In both developed and developing countries the share of public health expenditures for diabetes and obesity increases rapidly. This results in an intense expansion of research in the area of the pathogenesis of these diseases. Translational research which defines studies where knowledge obtained in research laboratories is used to understand the molecular bases of these diseases and implement it for clinical applications is a major part of efforts to have knowledge of and potentially cure obesity and diabetes. Additionally, there is a significant number of studies researching on the potential use of plants and plant extracts to cure these two metabolic anomalies. In this context, concepts of plant biotechnology and medicinal plants began to gain a special importance in the area. The supply of a considerable number of information based on translational and plant research on the field of diabetes and obesity made it inevitable to make use of the advantages of proteomics and bioinformatics. We in our mini review focused on the studies regarding obesity and diabetes in a frame of translational research and plant research. We also highlighted the importance of proteomics and bioinformatics for the systematic dissection of accumulated data on the pathogenesis of these diseases.
Three-dimensional quantitative structure activity relationship (3D-QSAR) analyses were carried out on a set of 42 xanthone derivatives in order to understand their anti-alpha glucosidic activities. The studies include Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Models with good predictive abilities were generated with the cross validated r2 (r2cv) values for CoMFA and CoMSIA being 0.580 and 0.610 respectively. The conventional r2 values were 0.949 each for both CoMFA and CoMSIA models. In addition, a homology model of human alpha glucosidase was used for docking based alignment of the compounds. The most active compound then served as a template for the alignment of the remaining structures in order to align all compounds prior to QSAR studies. Further, mapping of contours onto the active site validated each other in terms of residues involved with reference to respective contours. This integrated molecular docking based alignment followed by 3D-QSAR studies should provide further insights to support structure-based design of anti-diabetic agents with improved activity profiles.
The 70% EtOH extract of Scoparia dulcis showed inhibitory activity against beta-glucuronidase from bovine liver. Bioassay-directed fractionation of the active extract led to the isolation of three labdane-type diterpene acids, scoparic acid A {1} [6-benzoyl-12-hydroxy-labda-8(17), 13-dien-18-oic acid], scoparic acid B [2] [6-benzoyl-14,15-dinor-13-oxo-8(17)-labden-18-oic acid], and scoparic acid C [3] [6-benzoyl-15-nor-14-oxo-8(17)-labden-18-oic acid], the structures of which were established by spectral means, including X-ray analysis. Scoparic acid A was found to be a potent beta-glucuronidase inhibitor.
Production of scopadulcic acid B and scopadulciol by leaf organ culture of Scoparia dulcis was examined by addition of cytokinins to culture media. Of the tested cytokinins, N-phenyl-N′-(4-pyridyl)urea was the most efficient when supplemented in the mass spectroscopic liquid culture medium at 0.1 μM.
We investigated in vitro inhibition of mammalian carbohydrate-degrading enzymes by six-membered sugar mimics and their evaluation in cell cultures. 1-Deoxynojirimycin (DNJ) showed no significant inhibition toward glycogen phosphorylase (GP) but was a potent inhibitor of another glycogen-degrading enzyme, amylo-1,6-glucosidase (1,6-GL), with an IC50 value of 0.16 μM. In primary rat hepatocytes, the inhibition of glycogen breakdown by DNJ reached plateau at 100 μM with 25% inhibition and then remained unchanged. The potent GP inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (D-AB1) inhibited hepatic glucose production with an IC50 value of about 9 μM and the inhibition by D-AB1 was further enhanced in the presence of DNJ. DNJ and α-homonojirimycin (HNJ) are very potent inhibitors of rat intestinal maltase, with IC50 values of 0.13 and 0.08 μM, respectively, and also showed a similar strong inhibition toward maltase in Caco-2 cell model system, with IC50 value of 0.05 and 0.10 μM, respectively. D-Isofagomine (D-IFG) and L-IFG are competitive and noncompetitive inhibitors of human lysosomal β-glucosidase (β-GL), respectively, with Ki values of 8.4 nM and 6.9 μM. D-IFG increased intracellular β-GL activity by twofold at 10 μM in Gaucher N370S cell line as an ‘active-site-specific’ chaperone, and surprisingly a noncompetitive inhibitor L-IFG also increased intracellular β-GL activity by 1.6-fold at 500 μM.
Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol-redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9-aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9-aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed.
Scoparia dulcis is a perennial herb widely distributed in many tropical countries. It is used as an herbal remedy for gastrointestinal and many other ailments, and in Nicaragua extracts are used to treat malaria. Phytochemical screening has shown that scopadulcic acid A (SDA), scopadulcic acid B (SDB), and semisynthetic analogues are pharmacologically active compounds from S. dulcis. SDB has antiviral activity against Herpes simplex virus type 1, antitumor activity in various human cell lines, and direct inhibitory activity against porcine gastric H(+), K(+)-ATPase. A methyl ester of scopadulcic acid B showed the most potent inhibitory activity against gastric proton pumps of 30 compounds tested in one study. Compounds with antiviral, antifungal, and antitumor activity often show activity against Plasmodium falciparum. In P. falciparum, the plasma membrane and food vacuole have H(+)-ATPases and the acidocalcisome has an H(+)-Ppase. These proton pumps are potential targets for antimalarial therapy and may have their function disrupted by compounds known to inhibit gastric proton pumps. We tested pure SDA and found in vitro activity against P. falciparum with an IC(50) of 27 and 19 microM against the D6 and W2 clones, respectively. The IC(50) against the multidrug-resistant isolate, TM91C235, was 23 microM.
Anilinopyrazoles as CDK2 inhibitors can adopt multiple binding modes depending on the substituents at the 5-position of the pyrazole ring, based on CDK2/cyclin A crystallographic studies. Three commercially available docking programs, FlexX, GOLD, and LigandFit, were tested with 63 anilinopyrazole analogues in an attempt to reproduce the binding modes observed in the crystal structures. Each docking program gave different ligand conformations depending on the scoring or energy functions used. FlexX/drugscore, GOLD/chemscore, and LigandFit/plp were the best combinations of each docking program in reproducing the ligand conformations observed in the crystal structures. The 63 analogues were divided into two groups, type-A and type-B, depending on the substituent at the 5-position of the pyrazole ring. Although an alternate binding mode, observed in a crystal structure of one type-B compound, could not be reproduced with any of the above docking/scoring combinations, GOLD, with a template constraint based on the crystal structure coordinates, was able to reproduce the pose. As for type-A compounds, all docking conditions yielded similar poses to those observed in crystal structures. When predicting activities by scoring programs, the combination of docking with LigandFit/plp and scoring with LIGSCORE1_CFF gave the best correlation coefficient (r=0.60) between experimental pIC50 values and top-ranked rescores of 30 poses of each compound. With regard to type-A compounds, the correlation was 0.69. However, when 11 compounds, whose top-ranked rescored poses did not demonstrate the correct binding modes in reference to the crystal structure, were removed, the correlation rose to 0.75. Consequently, predicting activity on the basis of correct binding modes was found to be reliable.