In silico modeling and in vitro activity of vitexin and isovitexin against SGLT2

2019 ◽  
Vol 18 (07) ◽  
pp. 1950035
Author(s):  
Yongheng Shi ◽  
Fancui Meng ◽  
Jiping Liu ◽  
Bin Wang
Keyword(s):  
Homology Model ◽  
Binding Mode ◽  
Positive Control ◽  
Binding Energies ◽  
In Vitro Test ◽  
In Silico Modeling ◽  
Vitro Test ◽  
Dynamics Simulations ◽  
Molecular Docking And Dynamics

The homology model of hSGLT2 (human sodium dependent glucose co-transporter 2) was used as a target for diabetes mellitus. Molecular docking and dynamics simulations were carried out on vitexin- and isovitexin-SGLT2 complexes with dapagliflozin as positive control. The results show that both vitexin and isovitexin have weaker binding energies compared to dapagliflozin, indicating that both ligands may exhibit weak anti-diabetic effects through inhibiting SGLT2. The poor binding mode of vitexin and isovitexin may be responsible for their weak anti-diabetic effect. These results are in accordance with the inhibitory activity against hSGLT2 in vitro test with the inhibitory rate 26.3% of vitexin and 11.2% of isovitexin at the dose of 10[Formula: see text][Formula: see text]mol[Formula: see text][Formula: see text][Formula: see text]L[Formula: see text]. The results of calculation and in vitro test may explain the possible inhibiting mechanism of vitexin and isovitexin against SGLT2, and therefore enhance our understanding of the structure-activity relationships of SGLT2 inhibitors.

In silico modeling of aspalathin and nothofagin against SGLT2

2015 ◽  
Vol 14 (08) ◽  
pp. 1550056 ◽  
Author(s):  
Wei Liu ◽  
Huanjie Wang ◽  
Fancui Meng
Keyword(s):  
Positive Control ◽  
Binding Energies ◽  
Binding Modes ◽  
In Silico Modeling ◽  
Sodium Dependent ◽  
Sglt2 Inhibition ◽  
Calculation Results ◽  
Dynamics Simulations ◽  
Poor Absorption ◽  
Molecular Docking And Dynamics

Aspalathin and nothofagin are the major dihydrochalcones found in rooibos (Aspalathus linearis), which display anti-diabetic activities, but the mechanism is still unclear. In this paper, hSGLT2 (human sodium dependent glucose co-transporter 2), a target for diabetes mellitus, was built using homology modeling method. Molecular docking and dynamics simulations were carried out on aspalathin, nothofagin and SGLT2 complexes with dapagliflozin as positive control. The results show that both the binding energies and binding modes of aspalathin and nothofagin are similar to dapagliflozin, indicating that either component of rooibos may exhibit anti-diabetic effects through inhibiting SGLT2 receptor. However, the predicted permeability value of aspalathin and nothofagin is low, which may cause poor absorption, resulting in weak SGLT2 inhibition. Calculation results elucidate the possible inhibiting mechanism of aspalathin and nothofagin against SGLT2, and therefore enhance our understanding of anti-diabetic activities of rooibos.

scholarly journals Synthesis and evaluation trypanosomicidal activity of new derivatives of megazol

2018 ◽  
Vol 5 (2) ◽  
pp. 40
Author(s):  
Helena B. Leites ◽  
Flávia S. Damasceno ◽  
Ariel M. Silber ◽  
Ronaldo Z. Mendonça ◽  
Cristina Northfleet de Albuquerque
Keyword(s):  
Cell Proliferation ◽  
Positive Control ◽  
In Vitro Test ◽  
Biological Part ◽  
Amide Derivatives ◽  
Vitro Test ◽  
South Americans ◽  
Derivatives Of

Objective: This work aims at the synthesis of megazol analogs with antitrypanosomicidal activity. Chagas’disease is caused by Trypanosoma cruzi and is a debilitating disease that has both acute and chronic forms. Many South Americans suffer from the chronic form of Chagas’disease, and there is no treatment currently available.Methods: In the chemical part, classical techniques of heterocyclic synthesis as well as usual methods of identification were used. In the biological part the cell proliferation test was used in vitro and the IC 50.Results: We synthesized a series of derivatives of 2-(1-methyl-5-nitro-2-imidazolyl)-5-substituted-1,3,4-thiadiazoles where 1-acetyl, 1-propyl and 1-nonyl were used as the substituent (4,6,7). Derivatives without nitro group were also synthesized (3,12) along with thiosemicarbazones (8,9,10) and a 5-(5-nitro-2-furanyl)-1,3,4-thiadiazol-2-amine (11). These compounds were evaluated using an in vitro test where were measured the cell proliferation. The derivatives that obtained the best results underwent further tests, in which their IC50 was calculated. The data revealed that two compounds (4,6) were effective against the parasite (IC50= 0.354 µM; IC50= 2.13 µM) and besides that, obtained the same results as the positive control, antimycim and rotenone. All proposed structures were obtained in satisfactory yields and purities.Conclusions: In conclusion, the in vitro trypanocidal activity makes these compounds promising leads in the development of an effective therapeutic agent. However, this study must be completed by additional tests with in vitro amastigote/macrophage models or in vivo mouse models. Analyzing the amide derivatives, compounds (4) and (6) were the ones that presented the best results.

scholarly journals Discrimination of Naturally-Occurring 2-Arylbenzofurans as Cyclooxygenase-2 Inhibitors: Insights into the Binding Mode and Enzymatic Inhibitory Activity

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 176 ◽  
Author(s):  
Ericsson Coy-Barrera
Keyword(s):  
Three Dimensional ◽  
3D Qsar ◽  
Binding Mode ◽  
Binding Energies ◽  
Wide Range ◽  
Ic50 Values ◽  
Structure Relationship ◽  
Cox 2 ◽  
Dynamics Simulations

2-arylbenzofuran-containing compounds are chemical entities that can be naturally produced by several organisms. A wide-range of activities is described for several compounds of this kind and they are, therefore, valuable moieties for a lead finding from nature. Although there are in-vitro data about the activity of 2-arylbenzofuran-related compounds against cyclooxygenase (COX) enzymes, the molecular level of these COX-inhibiting constituents had not been deeply explored. Thus, 58 2-arylbenzofurans were initially screened through molecular docking within the active site of nine COX-2 crystal structures. The resulting docking scores were statistically analyzed and good reproducibility and convergence were found to discriminate the best-docked compounds. Discriminated compounds exhibited the best performance in molecular dynamics simulations as well as the most-favorable binding energies and the lowest in-vitro IC50 values for COX-2 inhibition. A three-dimensional quantitative activity-structure relationship (3D-QSAR) was also demonstrated, which showed some crucial structural requirements for enhanced enzyme inhibition. Therefore, four hits are proposed as lead structures for the development of COX-2 inhibitors based on 2-arylbenzofurans in further studies.

scholarly journals Antimalarial Activity of some Kaurenes

2017 ◽  
Vol 12 (2) ◽  
pp. 1934578X1701200
Author(s):  
Thayded Villasmil ◽  
Julio Rojas ◽  
Rosa Aparicio ◽  
Neira Gamboa ◽  
Maria Eugenia Acosta ◽  
...  
Keyword(s):  
Post Infection ◽  
Antimalarial Activity ◽  
Methyl Esters ◽  
Epoxy Group ◽  
Acid Methyl Ester ◽  
Positive Control ◽  
In Vitro Test ◽  
Vitro Test

The antimalarial activity of sixteen ent-kaurenes was assayed on male albino mice infected with Plasmodium berghei. Ent-kaur-16-en-19-oic acid (kaurenic acid), 15α-hydroxy- ent-kaur-16-en-19-oic acid, 15α-acetoxy- ent-kaur-16-en-19-oic acid, and ent-kaur-9(11)16-en-19-oic acid, natural kaurenes isolated from two species of Espelletiinae, were modified by semisynthesis to obtain methyl esters, glucopyranosyl esters, epoxides, 17-hydroxy, and isokaurenes (compounds with a 15,16-double bond). The kaurenes were first submitted to an in vitro test to measure their capacity to inhibit the formation of β-hematin. Compared with chloroquine (95.7%), the best effect was shown by 16,17-epoxy- ent-kauran-19-oic acid α-D-glucopyranosyl ester (2a), which produced 92.6% inhibition. Three other kaurenes showed good inhibition levels: ent-kaur-16-en-19-oic acid (1a, 73.5%), 17-hydroxy- ent-kaur-15-en-19-oic acid methyl ester (3b, 76.5%), and 15-oxo-16,17-epoxy- ent-kaur-16-en-19-oic acid α-D-glucopyranosyl ester (4b,76.1%). These four compounds were assayed in a four day suppressive test in vivo (Peters’ test) using chloroquine as a positive control Two hours after infection the mice received the first treatment and then every 24 hours during four consecutive days. Blood smears from the tails were prepared on the fourth day and parasitemia was determined microscopically. Survivals were followed up to the 30th day post-infection, Once again compound 2a performed best, showing 4.5% of parasitemia on the fourth day post-infection (chloroquine 0.2%) and a survival time of 25.5 days (chloroquine 29.5 days; 1a 18.8 days, 4b 12 7 days and 3b 10.3 days). A comparative examination of the effect of all compounds on the in vitro test permitted the inference that the presence of a C-19 carboxylic moiety was a requirement for the antimalarial activity and that a 16,17 epoxy group enhanced such activity.

scholarly journals ANALISIS FITOKIMIA DAN UJI POTENSI EKSTRAK BUAH RENGGAK (Amomum Dealbatum) SEBAGAI PESTISIDA NABATI TERHADAP JAMUR Pyricularia Oryzae DAN BAKTERI Xanthomonas oryzae

2020 ◽  
Vol 8 (1) ◽  
pp. 115
Author(s):  
Novita Hidayatun Nufus
Keyword(s):  
Antibacterial Activity ◽  
Ethanol Extract ◽  
Antibacterial Activities ◽  
Positive Control ◽  
Pyricularia Oryzae ◽  
Xanthomonas Oryzae ◽  
In Vitro Test ◽  
Paper Disk ◽  
Vitro Test

This study aims to determine the potency of Renggak (Amomum dealbatum) extract as bio pesticide against Pyricularia oryzae and Xanthomonas oryzae. Therefore an in vitro of  antifungal and antibacterial activity of the Renggak ethanol extract were carried out against Pyricularia oeyzae and Xanthomonas oryzae. In vitro antifungal  analysis were done using agar diffusing method by dissolving Renggak extract (1%, 5%, and 10%) into fungal medium and the growth of  Pyricularia oryzae were observed. In vitro antibacterial analysis were complited using agar diffusing method with paper disk that contain Renggak extract (10%, 20%, and 30%) and antibiotic chloroamfenikol as positive control. The result suggest that Renggak fruit extract has antifungal and antibacterial activities. The treatment with 10% Renggak extract could inhibit the growth of Pyricularia oryzae to 100%, same with positive control (Fungicide Score-250). In vitro test for antibacterial activity showed that treatments with 20% and 30% Renggak extract gave inhibitory activities that similar with positive control. Renggak ethanol extract gave positive results on Flavonoid, Alkaloid, Steroid, Terpenoid, and Saponin tests. GC-MS assays showed that Renggak ethanol extract produces at least 10 organic compounds that was identified as  2-butanone, 4-methoxypheyl, Benzenepropanoic-aci, 4-hydroxyphenil, CAS, octadecanoid acid, stearic acid, palmiti acid, Benzenepropanoic acid, dan Farnesol isomer A, which have antimicrobial avtivities.

scholarly journals Coumarins and Polar Constituents from Eupatorium triplinerve and Evaluation of Their α-Glucosidase Inhibitory Activity

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Do Thi Viet Huong ◽  
Phan Minh Giang ◽  
Vu Minh Trang
Keyword(s):  
2D Nmr ◽  
Positive Control ◽  
Water Soluble ◽  
In Vitro Test ◽  
Leaf Extracts ◽  
Ic50 Value ◽  
Vitro Test ◽  
High Concentrations ◽  
First Time

In our study of antidiabetic compounds from the leaves of Eupatorium triplinerve Vahl. (Asteraceae), ten compounds were isolated from the methanol leaf extract. They were determined to be β-sitosterol (1), stigmasterol (2), β-sitosterol 3-O-β-D-glucopyranoside (3), ayapanin (4), ayapin (5), thymoquinol 5-O-β-D-glucopyranoside (6), thyrsifloside (8), (E)-4-methoxymelilotoside (9), and kaempferol 3,7-di-O-β-D-glucopyranoside (10) by using ESI-MS, 1D (1H-, 13C-, DEPT) and 2D NMR (HSQC, HMBC, and NOESY) techniques. This is the first report of water-soluble compounds from E. triplinerve and compounds 6–10 were isolated for the first time from E. triplinerve. NMR profiling and HPLC analysis are fast and reliable methods to screen phytochemicals in plant samples. Due to their high concentrations in the leaf extracts of E. triplinerve, coumarins 4 and 5 could be fast screened by NMR profiling and RP-HPLC-PDA analysis. In the in vitro test for α-glucosidase inhibition of compounds 4–9, compounds 4, 5, and 7 showed the enzymatic inhibition of 40%, 46%, and 81%, respectively, at 256 μg/mL. An IC50 value of 58.65 ± 1.20 μg/mL (302 μM) was calculated for compound 7 which is lower than that of the positive control acarbose (IC50 197.33 ± 2.51 μg/mL; 306 μM).

Haemostatic Platelet Plug Formation in the Isolated Rabbit Mesenteric Preparation - An Analysis of Red Blood Cell Participation

1980 ◽  
Vol 44 (01) ◽  
pp. 006-008 ◽  
Author(s):  
D Bergqvist ◽  
K-E Arfors
Keyword(s):  
Whole Blood ◽  
Platelet Rich Plasma ◽  
Adenosine Diphosphate ◽  
In Vitro Test ◽  
Pharmacological Agents ◽  
Vitro Test ◽  
Releasing Effect ◽  
Plug Formation

SummaryIn a model using an isolated rabbit mesenteric preparation microvessels were transected and the time until haemostatic plugs formed was registered. Perfusion of platelet rich plasma gave no haemostasis whereas whole blood did. Addition of chlorpromazine or adenosine to the whole blood significantly prolonged the time for haemostasis, and addition of ADP to the platelet rich plasma significantly shortened it. It is concluded that red cells are necessary for a normal haemostasis in this model, probably by a combination of a haemodynamic and ADP releasing effect.The fundamental role of platelets in haemostatic plug formation is unquestionable but there are still problems concerning the stimulus for this process to start. Three platelet aggregating substances have been discussed – thrombin, adenosine diphosphate (ADP) and collagen. Evidence speaking in favour of thrombin is, however, very minimal, and the discussion has to be focused on collagen and ADP. In an in vitro system using polyethylene tubings we have shown that "haemostasis" can be obtained without the presence of collagen but against these results can be argued that it is only another in vitro test for platelet aggregation (1).To be able to induce haemostasis in this model, however, the presence of red blood cells is necessary. To further study this problem we have developed a model where haemostatic plug formation can be studied in the isolated rabbit mesentery and we have briefly reported on this (2).Thus, it is possible to perfuse the vessels with whole blood as well as with platelet rich plasma (PRP) and different pharmacological agents of importance.

IDENTIFICATION OF SELETIVE CLAUDIN CATION CHANNEL BLOCKERS

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S25-S26
Author(s):  
Jingjing Ma ◽  
Emma Wu ◽  
Ye Li ◽  
William Seibel ◽  
Le Shen ◽  
...  
Keyword(s):  
Small Molecules ◽  
Homology Model ◽  
Docking Studies ◽  
Channel Blockers ◽  
Binding Modes ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Dynamics Simulations ◽  
In Silico Models

Abstract Compromised epithelial barrier function is known to be associated with inflammatory bowel disease (IBD) and may contribute to disease development. One mechanism of barrier dysfunction is increased expression of paracellular tight junction ion and water channels formed by claudins. Claudin-2 and -15 are two such channels. We hypothesize that blocking these channels could be a viable therapeutic approach to treat diarrhea. In an effort to develop blockers of these channels, we turn to our previously developed and validated in silico models of claudin-15 (Samanta et al. 2018). We reasoned that compounds that can bind with the interior of claudin pores can limit paracellular water and ion flux. Thus, we used docking algorithms to search for putative small molecules that bind in the claudin-15 pore. AutoDock Vina was initially used to assess rigid docking using small compound databases. The small molecules were analyzed based on binding affinity to the pore and visualized using VMD for their potential blockage of the channel. Clusters of binding modes were identified based on the prominent interacting residues of the protein with the small molecules. We initially screened 10,500 compounds from within the UIC Centre for Drug Discovery and a cross-section of 10,000 compounds from the NCI open compound repository. This initial screen allowed us to identify 2 first-in-class selective claudin-15 blockers with efficacy in MDCK monolayers induced to express claudin-15 and in wildtype duodenum. Next, we screened the entire NCI open compound repository for additional molecules structurally related to our best initially identified molecule and this has allowed us to identify 13 additional molecules that increase TER of claudin-15 expressing MDCK monolayers by 90–160%. Additionally, these molecules possess similar structural components that will be collected in a fragment library and explored through molecular dynamics simulations. We also developed a claudin-2 homology model on which we are performing docking studies and in vitro measurements, which we expect will result in similar candidate ligands for blocking claudin-2. Our study will provide important insight into the role of claudin-dependent cation permeability in fundamental physiology, which we believe will lead to the utility of claudin blockers as a novel and much needed approach to treat diseases such as IBD.

scholarly journals In Vitro Newly Isolated Environmental Phage Activity against Biofilms Preformed by Pseudomonas aeruginosa from Patients with Cystic Fibrosis

2021 ◽  
Vol 9 (3) ◽  
pp. 478
Author(s):  
Ersilia Vita Fiscarelli ◽  
Martina Rossitto ◽  
Paola Rosati ◽  
Nour Essa ◽  
Valentina Crocetta ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
In Vitro Test ◽  
Chronic Infections ◽  
Hospital Environments ◽  
Vitro Test ◽  
General Reliability ◽  
Phage Activity

As disease worsens in patients with cystic fibrosis (CF), Pseudomonas aeruginosa (PA) colonizes the lungs, causing pulmonary failure and mortality. Progressively, PA forms typical biofilms, and antibiotic treatments determine multidrug-resistant (MDR) PA strains. To advance new therapies against MDR PA, research has reappraised bacteriophages (phages), viruses naturally infecting bacteria. Because few in vitro studies have tested phages on CF PA biofilms, general reliability remains unclear. This study aimed to test in vitro newly isolated environmental phage activity against PA isolates from patients with CF at Bambino Gesù Children’s Hospital (OBG), Rome, Italy. After testing in vitro phage activities, we combined phages with amikacin, meropenem, and tobramycin against CF PA pre-formed biofilms. We also investigated new emerging morphotypes and bacterial regrowth. We obtained 22 newly isolated phages from various environments, including OBG. In about 94% of 32 CF PA isolates tested, these phages showed in vitro PA lysis. Despite poor efficacy against chronic CF PA, five selected-lytic-phages (Φ4_ZP1, Φ9_ZP2, Φ14_OBG, Φ17_OBG, and Φ19_OBG) showed wide host activity. The Φ4_ZP1-meropenem and Φ14_OBG-tobramycin combinations significantly reduced CF PA biofilms (p < 0.001). To advance potential combined phage-antibiotic therapy, we envisage further in vitro test combinations with newly isolated phages, including those from hospital environments, against CF PA biofilms from early and chronic infections.

Sign in / Sign up

Export Citation Format

Share Document