Sivelestat (Neutrophil Elastase Inhibitor) as an Anti-inflammatory and Anti-viral Agent: An In Silico Study.

Background Sivelestat is a potent and specific neutrophil elastase inhibitor. It is clinically used in treating lung injury and respiratory distress syndrome. This engaged us to undertake the present study in which sivelestat was studied as an anti-inflammatory and anti-viral agent. Methodology The docking study of sivelestat on matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), chikungunya virus nonstructural protein-2 (CVnsP2) protease, and influenza A (H1N9) virus neuraminidase was assessed using the Chemistry at Harvard Macromolecular Mechanics (CHARMM) Dock (CDOCK) method. Furthermore, molecular physicochemical; bioactivity; absorption, distribution, metabolism, and excretion (ADME); toxicity; and Search Tool for Interacting Chemicals (STITCH) analyses were performed by using the Molinspiration (Molinspiration Cheminformatics, Slovensky Grob, Slovak Republic), SwissADME SwissADME (Swiss Institute of Bioinformatics, Quartier Sorge - Bâtiment Amphipôle, Switzerland), pkCSM (University of Melbourne, Melbourne, Australia), and STITCH-free online tools. Results The molecular physicochemical assessment of the ligand (sivelestat) showed no (zero) violation and agreed with the thumb rule of five, otherwise known as Lipinski's rule of five. ADME prediction of the ligand (sivelestat) is shown to possess a low gastrointestinal absorption (GIA) property. Similarly, toxicity analysis of the ligand (sivelestat) is predicted to have a hepatotoxicity effect. STITCH analysis reveals that the ligand (sivelestat) has exhibited interactions with the three human proteins. Conclusions The present molecular docking studies showed that the ligand (sivelestat) has successfully docked with all four enzymes of interest. Hence, the current finding has provided a good understanding of sivelestat as an effective suppressor activity against all four enzymes: MMP-2, MMP-9, CVnsP2 protease, and influenza neuraminidase.

In Silico Analysis of Selected Mikania Constituents As Human HMG-CoA Reductase, Human Inducible Nitric Oxide Synthase, and Human Squalene Synthase Inhibitory Agents.

Background Numerous pharmacological activities have been reportedin Mikania species. In the present investigation, we aimed to evaluate 26 selected constituents of Mikania as potent inhibitory agents of human HMG-CoA reductase (hHMGR), human inducible nitric oxide synthase (hiNOS), and human squalene synthase (hSQS) using the in silico method. Methodology Twenty-six selected constituents of Mikania were investigated based on the docking behavior of three target enzymes, namely hHMGR, hiNOS, and hSQS, using the Cdocker method (Discovery Studio® 3.1, Accelrys, Inc., San Diego, CA). Results Docking analysis showed that methyl-3,5-di-O-caffeoyl quinate (MCQ) has the maximum binding energy (BE) (-39.63, -50.65, and -58.56 kcal/mol) with hHMGR, hiNOS, and hSQS enzymes. On the other hand, six ligands (kaurenoic acid (KAA), stigmasterol (SS), grandifloric acid (GA), kaurenol (KA), spathlenol (SP), and taraxerol (TA)) of Mikania failed to dock with either of the target enzymes (hHMGR, hiNOS, or hSQS). Conclusions The findings of the current study provide new insight regarding 26 selected ligands of Mikania as potent inhibitory agents of hHMGR, hiNOS, and hSQS.

In Silico Analysis of Selected Glycyrrhiza glabra (Licorice) Constituents: Exploring Their Modulatory Effects on Human Superoxide Dismutase, Human Phosphodiesterase-9 and Human Dipeptidyl Peptidase-4.

Background Glycyrrhiza glabra (Licorice) has been known for its various biological activities. In the current investigation, we aimed to evaluate 11 (10 natural and one synthetic) selected constituents of G. glabra as potent modulatory agents of human superoxide dismutase (hSOD), human phosphodiesterase-9 (hPDE 9) and human dipeptidyl peptidase-4 (hDPP 4) using in silico method. Methodology The 11 selected constituents of G. glabra (Licorice) were investigated on the docking behaviour of hSOD, hPDE 9 and hDPP 4 by using the PatchDock method. In addition to docking, toxicity analysis was also carried out using the pkCSM free online server (University of Melbourne, Melbourne, AUS). Results Toxicity analysis has shown that four ligands (36%) of G. glabra (Licorice) are predicted to have human ether-a-go-go-related gene-2 (hERG 2) inhibition activity. The docking analysis showed that glabridin (-224.13 kcal/mol) has shown the highest atomic contact binding energy with the hSOD enzyme, whereas carbenoxolone has shown the maximum atomic contact binding energy with both the hPDE 9 and hDPP 4 enzymes (-239.57 and -173.50 kcal/mol) respectively. Conclusion Thus the present finding provides new information about 11 selected ligands of G. glabra (Licorice) as potent modulatory agents of hSOD, hPDE 9 and hDPP 4.

Molecular Docking Analysis of Selected Urtica dioica Constituents As Human Carbonic Anhydrase II (hCA-II), Human 11 Beta-Hydroxysteroid Dehydrogenases Type 1 (h11beta-HSD1), and Human Dual Specificity Phosphatase (hCDC25B) Inhibitory Agents.

Background Urtica dioica (Stinging nettle)has been reported to exhibit various pharmacological activities. In the present study, we aimed to evaluate 24 selected constituents of U. dioica as potent inhibitory agents of human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11beta-HSD1), and human dual specificity phosphatase (hCDC25B) using in silico method. Methodology The 24 selected constituents of U. dioica (Stinging nettle) were studied on the docking behavior of hCA-II, h11beta-HSD1, and hCDC25B by using the Webina docking method. In addition to docking, toxicity analysis was also performed using the pkCSM free web server, respectively. Results Toxicity analysis has shown that six ligands (25%) of U. dioica (Stinging nettle) are predicted to have hERG II (Human ether-a-go-go-related gene) inhibition activity. The docking analysis showed that afzelin, stigmastane-3, 6-diol, and astragalin of U. dioica have shown the maximum binding energy (-7.2, -9.5, and -8.5 kcal/mol) with the hCA-II, h11beta-HSD1 and hCDC25B, respectively. Conclusions Thus, the current finding provides new knowledge about the 24 selected ligands of U. dioica (Stinging nettle) as potent inhibitory agents of human carbonic anhydrase II (hCA-II), human 11 beta-hydroxysteroid dehydrogenases type 1 (h11beta-HSD1) and human dual specificity phosphatase (hCDC25B).

GC-MS, alpha-amylase, and alpha-glucosidase inhibition and molecular docking analysis of selected phytoconstituents of small wild date palm fruit (Phoenix pusilla).

Phoenix pusilla (Arecaceae), commonly known as "small wild date palm", is regarded as one of the underutilized fruit crops in South India. Methanol extract of P. pusilla ripened fruits (PPRF) was analyzed for in vitro porcine pancreatic alpha-amylase (PPAA) and rat small intestine alpha-glucosidase (RIAG) inhibition activities, and through gas chromatography-mass spectrometry (GC-MS) analysis. The GC-MS analysis showed the presence of 25 phytoconstituents from PPRF which was further assessed on the docking behavior of five targeted enzymes diabetes mellitus (DM) namely (i) human aldose reductase, (ii) protein tyrosine phosphatase 1B, (iii) pancreatic alpha-amylase, (iv) peroxisome proliferator-activated receptor gamma, and (v) dipeptidyl peptidase IV by using the AutoDock Vina method. In addition to this physicochemical, bioactivity score, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis was performed using the Molinspiration and pkCSM free online servers. Methanolic extract of PPRF showed 50% inhibition concentration (IC50) at 69.86 and 72.60 µg/mL levels against PPAA and RIAG enzymes activities, respectively. Interestingly in the present study, GC-MS analysis showed the presence of 25 phytoconstituents from PPRF. Physicochemical analysis of PPRF has exhibited that 13 ligands have complied well with Lipinski's Rule of Five (RoF). With regard to ADMET analysis, one ligand (9,12-octadecadienoic acid [Z,Z]) has predicated to possess both the hepatotoxicity (HT) and skin sensitization (SS) effect. The docking studies showed that 1-formyl-2,5-dimethoxy-6,9,10-trimethyl-anthracene exhibited the maximum atomic contact energy (ACE) for all the five target enzymes of DM. Thus, the current study suggested that the methanolic extract of PPRF and its phytoconstituents could be considered as potent antidiabetic agents.

An In Silico Analysis of Synthetic and Natural Compounds as Inhibitors of Nitrous Oxide Reductase (N2OR) and Nitrite Reductase (NIR).

Nitrification inhibitors are recognized as a key approach that decreases the denitrification process to inhibit the loss of nitrogen to the atmosphere in the form of N2O. Targeting denitrification microbes directly could be one of the mitigation approaches. However, minimal attempts have been devoted towards the development of denitrification inhibitors. In this study, we aimed to investigate the molecular docking behavior of the nitrous oxide reductase (N2OR) and nitrite reductase (NIR) involved in the microbial denitrification pathway. Specifically, in silico screening was performed to detect the inhibitors of nitrous oxide reductase (N2OR) and nitrite reductase (NIR) using the PatchDock tool. Additionally, a toxicity analysis based on insecticide-likeness, Bee-Tox screening, and a STITCH analysis were performed using the SwissADME, Bee-Tox, and pkCSM free online servers, respectively. Among the twenty-two compounds tested, nine ligands were predicted to comply well with the TICE rule. Furthermore, the Bee-Tox screening revealed that none of the selected 22 ligands exhibited toxicity on honey bees. The STITCH analysis showed that two ligands, namely procyanidin B2 and thiocyanate, have interactions with both the Paracoccus denitrificans and Hyphomicrobium denitrificans microbial proteins. The molecular docking results indicated that ammonia exhibited the second least atomic contact energy (ACE) of -15.83 kcal/mol with Paracoccus denitrificans nitrous oxide reductase (N2OR) and an ACE of -15.20 kcal/mol with Hyphomicrobium denitrificans nitrite reductase (NIR). The inhibition of both the target enzymes (N2OR and NIR) supports the view of a low denitrification property and suggests the potential future applications of natural/synthetic compounds as significant nitrification inhibitors.

Systematic induced resistance in Solanum lycopersicum (L.) against vascular wilt pathogen (Fusarium oxysporum f. sp. lycopersici) by Citrullus colocynthis and Trichoderma viride.

The antifungal effects of Citrullus colocynthis extract (Hexane, chloroform, methanol, and water) were tested in vitro on Fusarium oxysporum f. sp. lycopersici (Sacc.) W. C. Snyder & H. N. Hans (FOL), the causal agent of Fusarium wilt. Of these, methanol and water extract at 10% showed the highest inhibition of mycelial growth of FOL by 12.32 and 23.61 mm respectively. The antifungal compounds were identified through Fourier transform infrared (FT-IR) spectroscopy and gas chromatography-mass spectroscopy (GC-MS). The methanol extract was compatible with the biocontrol agent Trichoderma viride. The antagonistic fungi were mass-cultured under laboratory conditions using sorghum seeds. Both T. viride and C. colocynthis methanol extract was also tested alone and together against FOL under both in vitro and in vivo conditions. The combination of T. viride and C. colocynthis showed the highest percentage of antifungal activity (82.92%) against FOL under in vitro conditions. This study revealed that induced systemic resistance (ISR) in enhancing the disease resistance in tomato plants against Fusarium wilt disease. The combined treatment of T. viride and C. colocynthis significantly reduced the disease incidence and index by 21.92 and 27.02% in greenhouse conditions, respectively. Further, the induction of defense enzymes, such as peroxidase (PO), polyphenol oxidase (PPO), ß-1,3-glucanase, and chitinase were studied. The accumulation of defense enzyme was greater in plants treated with a combination of T. viride and C. colocynthis compared to the control. Reduction of wilt disease in tomato plants due to the involvement of defense-related enzymes is presumed through this experiment.

Identification of novel inhibitor against human phosphoethanolamine cytidylyltransferase from phytochemicals of Citrus sinensis peel extract by in vitro and in silico approach.

Kidney stone is a major global menace that demands research on nonsurgical treatment involving biological compounds for the benefit of the patients. Among the biological extracts, citric acid is traditionally used to dissolve kidney stones. The current research focuses on evaluating the in vitro anti-urolithiatic activity and in silico study of ethanolic extract of Citrus sinensis (ECS) peel against c: phosphoethanolamine cytidylyltransferase (PCYT). The diuretic activity was evaluated using in vitro model against the synthesized calcium oxalate crystals and cytotoxicity study in Madin-Darby canine kidney cell lines. The phytochemicals were identified using gas chromatography-mass spectroscopy. The interaction mechanism was studied using computational docking studies to confirm their involvement in the dissolution of calcium oxalate kidney stones. Further molecular properties, drug-likeness, ADME (absorption, distribution, metabolism, and excretion), and toxicity analysis were followed for the ligands using software tools. 5-Hydroxymethylfurfural, 2,4-di-tert-butylphenol, 2-methoxy-4-vinylphenol, 6-octen-1-ol, 3,7-dimethyl-, acetate (citronellyl acetate), 3',5'-dimethoxyacetophenone, and ethyl alpha-d-glucopyranoside showed good binding affinities against PCYT. Moreover, the docking studies showed the ligand 3',5'-dimethoxyacetophenone has the highest binding energy (-6.68 kcal/mol) for human CTP. The present investigation concludes that these compounds of C. sinensis peel extract compounds are responsible as novel inhibitors against human CTP and extend their use in the pharmaceutical drug development process.

In Silico Analysis of Cissus rotundifolia Constituents as Human Neutrophil Elastase (HNE), Matrix Metalloproteinases (MMP 2 and MMP 9), and Tyrosinase Inhibitors.

Cissus rotundifolia has been reported to possess various biological activities such as anti-diabetic, anti-fertility, anti-hyperlipidemic, anti-malarial, anti-osteoporotic, and anti-parasitic activities. Therefore in the present study, eleven selected constituents of Cissus rotundifolia which includes aconitic acid, astragalin, acteoside, aliospiroside A, beta amyrin, bergenin, formononetin, gallic acid, isovitexin, isoorientin, and isoquercitrin were studied on the docking behavior of human neutrophil elastase (HNE), matrix metalloproteinases (MMP 2 and MMP 9), and tyrosinase by using PatchDock method. Furthermore, molecular physicochemical, bioactivity score/drug-likeness, ADME (absorption, distribution, metabolism, and excretion), and toxicity analyses were also carried out using Molinspiration, Swiss ADME, and ProTox-II methods, respectively. The molecular physicochemical investigation showed that three ligands such as acteoside, aliospiroside A, and isoorientin have three violations for Lipinski's rule of five. Similarly, ADME analysis one ligand (formononetin) predicated to have high blood-brain barrier (BBB) permeability effect. The docking studies showed that isovitexin exhibited the highest atomic contact energy (-341.61 kcal/mol) for human neutrophil elastase (HNE), more over alliospiroside A has shown maximum atomic contact energy for both matrix metalloproteinases (MMP 2 [-618.00 kcal/mol] and MMP 9 [-634.73 kcal/mol]). Furthermore, isoquercitrin has exhibited the highest atomic contact energy (-145.70 kcal/mol) for tyrosinase. Thus, the present investigation outcome provides new knowledge in understanding eleven Cissus rotundifolia constituents as possible novel inhibitors against HNE, MMP 2, MMP 9, and tyrosinase.

Toxicity of Bioactive Molecule Andrographolide against Spodoptera litura Fab and Its Binding Potential with Detoxifying Enzyme Cytochrome P450.

Spodoptera litura Fab. is a polyphagous pest causing damage to many agriculture crops leading to yield loss. Recurrent usage of synthetic pesticides to control this pest has resulted in resistance development. Plant-derived diterpenoid compound andrographolide was isolated from the leaves of Andrographis paniculata. It was analysed by gas chromatography-mass spectroscopy and quantified by HPLC. Nutritional indices and digestive enzymatic profile were evaluated. Third, fourth and fifth instar larvae were treated with different concentrations of andrographolide. At 3, 6 and 9 ppm-treated concentrations the larvae showed decreased RGR, RCR, ECI, ECD values with adverse increase in AD. The digestive enzymes were significantly inhibited when compared with control. Conspicuously, andrographolide showed pronounced mortality of S. litura by inhibition of enzyme secretion and intake of food. The binding ability of andrographolide with CYTP450 showed high affinity with low binding energy. Andrographolide has the potential to be exploited as a biocontrol agent against S. litura as an eco-friendly pesticide.

Pyrene-based prospective biomaterial: In vitro bioimaging, protein binding studies and detection of bilirubin and Fe3.

Herein, we have meticulously derived the nanosized fluorescent aggregates from pyrene Schiff base (PS) in DMSO:water (10:90) ratio. The aggregation property of PS molecule was characterized by SEM and TEM measurements, revealed the aggregated particles are in spherical shape with ~3 nm in size. Moreover, aggregates exhibit a high fluorescence quantum yield (48%) which was effectively used for the in vitro bioimaging of two different cancer cells such as A549 and MCF-7 cells in which it exhibiting excellent biocompatibility. Further, it was estimated the capability of twofold acridine orange/ethidium bromide (AO/EB) staining to identify the apoptotic associated changes in cancer cells. Additionally, the aggregates were successfully demonstrated as a luminescent probe for the perceptive biomolecule detection of bilirubin. On the other hand, the PS molecule was successfully utilized for protein binding and metal ion sensing studies. The interaction of bovine serum albumin (BSA) with PS molecule in DMSO was using fluorescence spectroscopic method and nature of interaction was also confirmed through molecular docking analysis. The PS molecule also acts as an excellent sensor for biologically important Fe3+ ion with detection limit of 336 nM. Overall, PS molecule can be a prospective material in biological field both in solution as well as aggregated forms.

Asperyellone prevents HDF cells from UVB irradiation damages: An elaborated study.

The current study explores the photo-protective effect of asperyellone (AY) (a fungal secondary metabolite), assessed under in vitro condition using human dermal fibroblast cell line. AY was isolated from Aspergillus sp. during the resting phase and purified. The initial cytocompatibility assessment on concentrations of AY and the duration of exposure of UVB irradiations were studied respectively. N-acetyl-L-cysteine (NAC) was used as positive control. Cells were then pretreated with optimized concentration of AY (2.0 µM) and NAC (1 mM) for 1 hour and then UVB irradiated (30 mJ/cm 2 ) for the period of 10 minutes. Results revealed that reactive oxygen species generated upon UVB irradiation found scavenged by the AY pretreatment at a significant level. Furthermore, an appreciable reduction in apoptotic cell count and DNA damages support the scavenging effect of AY. Assessments on the expression of enzymatic and nonenzymatic antioxidants evidently prove the protective role of AY. The reduced expression levels of inflammatory markers (TNF-α and COX-2), collagen degraders (MMP 2 and MMP 9), apoptotic protein expressions (Bax and Bcl-2), and cell-cycle arrest analyses substantiate the photo-protective effect of AY similar to NAC (positive control). Thus, the observations made in the current study indicate the possible role of AY as a photo-protective agent.

Molecular Docking Analysis of Phytic Acid and 4-hydroxyisoleucine as Cyclooxygenase-2, Microsomal Prostaglandin E Synthase-2, Tyrosinase, Human Neutrophil Elastase, Matrix Metalloproteinase-2 and -9, Xanthine Oxidase, Squalene Synthase, Nitric Oxide Synthase, Human Aldose Reductase, and Lipoxygenase Inhibitors.

BACKGROUND: The phytoconstituents phytic acid and 4-hydroxyisoleucine have been reported to posses various biological properties. OBJECTIVE: This prompted us to carry out the docking study on these two ligands (phytic acid & 4-hydroxyisoleucine) against eleven targeted enzymes. MATERIALS AND METHODS: Phytic acid & 4-hydroxyisoleucine were evaluated on the docking behaviour of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), tyrosinase, human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), xanthine oxidase (XO), squalene synthase (SQS), nitric oxide synthase (NOS), human aldose reductase (HAR) and lipoxygenase (LOX) using Discovery Studio Version 3.1 (except for LOX, where Autodock 4.2 tool was used). RESULTS: Docking and binding free energy analysis revealed that phytic acid exhibited the maximum binding energy for four target enzymes such as COX-2, mPGES-2, tyrosinase and HNE. Interestingly, we found that 4-hydroxyisoleucine has the potential to dock and bind with all of the eleven targeted enzymes. CONCLUSION: This present study has paved a new insight in understanding 4-hydroxyisoleucine as potential inhibitor against COX-2, mPGES-2, tyrosinase, HNE, MMP 2, MMP 9, XO, SQS, NOS, HAR and LOX. SUMMARY: 4-hydroxyisoleucine has the potential to dock and bind with all 11targeted enzymes such as (cyclooxygenase-2 [COX-2], microsomal prostaglandin E synthase-2 [mPGES-2], tyrosinase, human neutrophil elastase [HNE], matrix metalloproteinase [MMP-2 and -9], xanthine oxidase, squalene synthase, nitric oxide synthase, human aldose reductase, and lipoxygenase)Moreover, docking studies and binding free energy calculations revealed that phytic acid exhibited the maximum binding energy for four target enzymes such as COX-2, mPGES-2, tyrosinase, and HNE; however, for other six target enzymes, it fails to dock. Abbreviations used: COX-2: Cyclooxygenase-2, mPGES-2: Microsomal prostaglandin E synthase-2, HNE: Human neutrophil elastase, MMP-2 and -9: Matrix metalloproteinase-2 and -9, XO: Xanthine oxidase, SQS: Squalene synthase, NOS: Nitric oxide synthase, HAR: Human aldose reductase, LOX: Lipoxygenase, ADME: Absorption, distribution, metabolism, and excretion, TOPKAT: Toxicity Prediction by Computer-assisted Technology.

Molecular Docking Analysis of Selected Clinacanthus nutans Constituents as Xanthine Oxidase, Nitric Oxide Synthase, Human Neutrophil Elastase, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9 and Squalene Synthase Inhibitors.

BACKGROUND: Clinacanthus nutans (Burm. f.) Lindau has gained popularity among Malaysians as a traditional plant for anti-inflammatory activity. OBJECTIVE: This prompted us to carry out the present study on a selected 11 constituents of C. nutans which are clinacoside A-C, cycloclinacoside A1, shaftoside, vitexin, orientin, isovitexin, isoorientin, lupeol and ß-sitosterol. MATERIALS AND METHODS: Selected 11 constituents of C. nutans were evaluated on the docking behavior of xanthine oxidase (XO), nitric oxide synthase (NOS), human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), and squalene synthase (SQS) using Discovery Studio Version 3.1. Also, molecular physicochemical, bioactivity, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and toxicity prediction by computer assisted technology analyzes were also carried out. RESULTS: The molecular physicochemical analysis revealed that four ligands, namely clinacoside A-C and cycloclinacoside A1 showed nil violations and complied with Lipinski's rule of five. As for the analysis of bioactivity, all the 11 selected constituents of C. nutans exhibited active score (>0) toward enzyme inhibitors descriptor. ADMET analysis showed that the ligands except orientin and isoorientin were predicted to have Cytochrome P4502D6 inhibition effect. Docking studies and binding free energy calculations revealed that clinacoside B exhibited the least binding energy for the target enzymes except for XO and SQS. Isovitexin and isoorientin showed the potentials in the docking and binding with all of the six targeted enzymes, whereas vitexin and orientin docked and bound with only NOS and HNE. CONCLUSION: This present study has paved a new insight in understanding these 11 C. nutans ligands as potential inhibitors against XO, NOS, HNE, MMP 2, MMP 9, and SQS. SUMMARY: Isovitexin and isoorientin (Clinacanthus nutans constituent) showed potentials in the docking and binding with all of the six targeted enzymes (xanthine oxidase [XO], nitric oxide synthase [NOS], human neutrophil elastase [HNE], matrix metalloproteinase [MMP 2 and 9], and squalene synthase [SQS])Moreover, clinacoside B (C. nutans constituent) exhibited the least binding energy for the target enzymes except for XO and SQSInterestingly, all of the selected ligands from C. nutans showed the potential to dock and bind with HNE. Abbreviations used: C. nutans: Clinacanthus nutans, XO: Xanthine oxidase, NOS: Nitric oxide synthase, HNE: Human neutrophil elastase, MMP: Matrix metalloproteinase, SQS: Squalene synthase, ADMET: Absorption, Distribution, Metabolism, Excretion, and Toxicity, TOPKAT: Toxicity prediction by the computer assisted technology.

Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor.

The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX) inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31-27.61 µM) where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs) and aromatic groups could significantly affect the enzymatic activity.

Inhibition of Angiogenesis and Nitric Oxide Synthase (NOS), by Embelin & Vilangin Using in vitro, in vivo & in Silico Studies.

PURPOSE: In recent year's anti-angiogenesis agents have been recognized as effective drugs for the treatment of solid tumors, this prompted us to conduct the present study. METHODS: The anti-angiogenic activity of dimeric form of embelin (vilangin) was evaluated using endothelial cell (in vitro) and chorioallantoic membrane (CAM) egg yolk angiogenesis model (in vivo) and in addition the docking behaviour of human nitric oxide synthases (NOS) with four different ligands was evaluated along with their putative binding sites using Discovery Studio Version 3.1 (in silico) compared with the parent compound (embelin). RESULTS: Vilangin exhibits 50% cytotoxic at 92 ± 1 µg/ml concentration level with reference to ECV 304 endothelial cells. Both vilangin and embelin, showed inhibitory effects on wound healing, single cell migration, nitric oxide production, and endothelial ring formation at 0.1 and 1.0 µg/ml concentration level. Similarly, CAM assay also showed inhibitory effect of vilangin and embelin with respect their reduction in length, size and junctions of blood capillaries compared to untreated egg yolk. Docking studies and binding free energy calculations revealed that vilangin has maximum interaction energy (-74.6 kcal/mol) as compared to the other investigated ligands. CONCLUSION: The results suggest that both vilangin and embelin attenuates angiogenesis in similar manner.