Potent Inhibitor Of Enzyme Research Articles

Functional and Bioactive Properties of Wheat Protein Fractions: Impact of Digestive Enzymes on Antioxidant, α-Amylase, and Angiotensin-Converting Enzyme Inhibition Potential.

This research aimed to determine the biofunctional properties of wheat flour (WF) protein fractions and modifications to the antioxidant, anti-α-amylase and anti-angiotensin-I converting enzyme (ACE) activities induced by the action of digestive endopeptidases in vitro. A molecular characterization of the most abundant protein fractions, i.e., albumins, glutelins-1, glutelins-2 and prolamins, showed that low- and high-MW polypeptides rich in cysteine, glutamic acid and leucine were present in albumins and glutelins, whereas low-MW subunits with a high proportion of polar amino acids prevailed in prolamins. Prolamins exhibited the second-highest water holding capacity (54%) after WF (84%), while albumins provided superior foam stability (76%). Prolamins, glutenins-1 and globulins demonstrated the highest antioxidant activity (up to 95%, 68% and 59%, respectively) both before and after hydrolysis with pepsin (P-H) or trypsin-chymotrypsin (TC-H). Prolamins, globulins and WF strongly inhibited α-amylase (>90%) before and after TC-H, and before P-H (55-71%). Moreover, P-H significantly increased α-amylase inhibition by albumins from 53 to 74%. The fractions with strong ACE inhibitory activity (70-89%) included prolamins and globulins after TC-H or P-H, as well as globulins before TC-H and WF before P-H. This novel evidence indicates that WF protein fractions and their peptide-enriched P and TC hydrolysates are excellent sources of multifunctional bioactives with antioxidant, antihyperglycemic and antihypertensive potential.

Antioxidant and Enzyme Inhibitory Activities of Rhoifolin Flavonoid: In Vitro and in Silico Studies.

Rhoifolin (apigenin-7-O-β-neohesperidoside) belongs to the class of flavonoids and was reported to exhibit anti-inflammatory, cytotoxic, antidiabetic, hepatoprotective, and cardioprotective activities. The current study presents the in-vitro evaluation of the antioxidative effects of rhoifolin by many assays, namely DPPH, CUPRAC, ABTS, phosphomolybdenum, and FRAP. Enzyme inhibitory potential was also evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, amylase, and glucosidase enzymes. While results revealed weak antioxidant activities for rhoifolin, the compound demonstrated some promising enzyme inhibitory effects against BChE (4.03 mg GALAE/g) and tyrosinase (7.44 mg KAE/g) but was not active on AChE. Regarding anti-diabetic enzymes, the compound was active on amylase but did not show any inhibition effect on glucosidase. In-silico molecular docking study was performed for rhoifolin on the active site of NADPH oxidase, BChE, and amylase enzymes to verify the observed enzyme inhibitory effect. Good binding affinities were observed for rhoifolin on all the docked enzymes, revealing numerous hydrogen bonds, carbon-hydrogen, van der Waals interactions. This is the first study to evaluate the enzyme inhibition potential of rhoifolin. We concluded that the increase in the degree of glycosylation might decrease the antioxidant abilities of flavonoids and that rhoifolin had moderate enzyme inhibition abilities to be investigated in future studies.

Antioxidant and Enzyme Inhibitory Potential of Streptomyces sp. G-18 Grown in Various Media.

Streptomyces are bacteria well known for producing bioactive secondary metabolites which are commonly found in diverse habitats. The biosynthesis of metabolites from Streptomyces is influenced by various factors such as the growth medium, environmental conditions, and gene regulation. This study aimed to investigate the influence of different growth media on biomass production and the antioxidant and enzyme inhibitory potential of a crude extract obtained from Streptomyces sp. G-18 isolated from high altitudinal soil of Nepal. The highest dry weight growth was observed in R2YE medium (184 mg/L), followed by R5 (144 mg/L), YEME (38 mg/L), and R5M media (30 mg/L). The crude extract showed notable antioxidant activities against free radicals. The highest alpha-amylase inhibition was observed in the R2YE medium, and worthy lipase and tyrosinase inhibition was observed in the YEME medium. However, only the R2YE medium exhibited inhibitory potential against elastase and acetylcholinesterase, while crude extracts from R5, YEME, and R5 modified did not show any such activity. Overall, our findings suggest that the production of bioactive secondary metabolites in Streptomyces sp. G-18 was significantly influenced by the growth medium. This strain may be a promising source of enzyme inhibitors with potential applications in the pharmaceutical and cosmetic industries.

Natural Anthraquinones as Promising MAPK3 Inhibitors for Complementary Cancer Therapy

Objective. MAPK3 activates several nuclear transcription factors, including c-Jun and c-fos, by phosphorylating its downstream cytoplasmic protein, thereby contributing to cell proliferation and survival. Different carcinomas’ initiation, progression, cancer cell metastasis, and drug resistance have been associated with MAPK3 overexpression. Given the need for new and potent MAPK3 inhibitors, this study aimed to explore the potential of anthraquinones (AQs) as organic compounds capable of inhibiting MAPK3. Methods. Using AutoDock 4.0 software, the binding affinity of 21 AQs to the receptor’s active site was evaluated. AQs were ranked based on their ΔGbinding values to the receptor’s active site, with the highest rankings receiving the most favorable scores. The Discovery Studio Visualizer tool was used to demonstrate the interaction modes between the highest-ranked AQs and the MAPK3 catalytic site. Furthermore, a 100-nanosecond molecular dynamics (MD) computer simulation was performed to assess the stability of the docked pose of the most potent enzyme inhibitor identified in this study. Results. The binding affinity of emodin-8-glucoside, aloe-emodin 8-glucoside, pulmatin, rhodoptilometrin, and hypericin to the receptor’s ATP binding cleft was noteworthy, as the ΔGbinding values were < − 10 kcal/mol. In addition, emodin-8-glucoside, aloe-emodin 8-glucoside, and pulmatin were found to have inhibition constant values at the picomolar concentration. According to our computer simulation results, the docked pose of emodin-8-glucoside within the active site of MAPK3 achieved a stable state after 70 ns. In other words, the root mean square deviation (RMSD) graph indicated stability within the 70–100 ns timeframe. Conclusion. Inhibition of MAPK3 by emodin-8-glucoside, aloe-emodin 8-glucoside, pulmatin, rhodoptilometrin, and hypericin may have therapeutic potential in cancer treatment.

Natural Products from Red Algal Genus Laurencia as Potential Inhibitors of RdRp and nsp15 Enzymes of SARS-CoV-2: An In Silico Perspective

The genus Laurencia, a category of marine red algae, is well recognized for producing a large variety of natural products (NPs) that are both chemically intriguing and structurally distinct. The aim of this research was to identify NPs with potential anti-SARS-CoV-2 activity. The crystals of the proteins RdRp and nsp15 were obtained from the RCSB protein database. About 300 NPs were discovered using the PubChem, ChemSpider, and CMNPD databases. The program Autodock Vina was used to conduct the molecular docking procedure once the proteins and ligands were prepared. Before running MD simulations using the CABS-flex 2.0 website, binding affinity assessments and interactions between amino acids were carefully reviewed. Only nine NPs were shortlisted to be examined further. Bromophycolide R, S, and bromophycoic acid C show the tendency to inhibit RdRp by β-hairpin motif binding at the N-terminal known as Active site 2 (AS2), whereas the other four NPs, bromophycolide E, H, P, and thyrsenol A, may effectively inhibit RdRp through interactions via C-terminal, also known as the Active site 1 (AS1). For the enzyme nsp15, bromophycoic B, C, and floridoside showed plausible interactions. In conclusion, out of nine, seven candidates shortlisted for RdRp exhibited strong interactions with the key residues in the AS1 and AS2 regions. Bromophycoic acid C may work as a dual inhibitor due to its favorable interactions with the nsp15 protein and RdRp’s N-terminal, with affinities of −8.5 and −8.2 kcal/mol, respectively.

Unveiling the phytochemical and pharmacological potential of Mimusops maxima (Poiret) Vaughan-an endemic plant with potential therapeutic effects

Mimusops maxima (Poiret) Vaughan is an endemic plant of Mauritius Island that has never been studied for neither its phytochemical nor pharmacological properties. Hence this study targeted to extract the phytochemicals using three different solvents and characterizion them through HPLC-MS-MS, alongside investigating their effects against chronic diseases. The methanolic extract beared the highest total phenolic and total flavonoid composition, (31.10 ± 0.25 gallic acid equivalents/gram (GAE/g) and 38.68 ± 0.34 rutin equivalent (mgRE/g)), respectively), succeeded by the ethyl acetate and aqueous extracts. The antioxidant assay demonstrated that the methanolic extract had the highest potency in terms of antioxidant potential. The most potent acetylcholinesterase enzyme inhibitor was the ethyl acetate extract (4.78 ± 0.28 mg GALAE/g) followed by the methanolic extract (4.48 ± 0.05 mgGALAE/g). The most inhibition of the tyrosinase enzyme was generated by the methanolic extract (122.53 ± 2.72 mg KAE/g),the ethyl acetate extract and aqueous extracts (113.96 ± 1.53 and 6.19 ± 0.30 mg KAE/g, respectively) followed and were behind the methanolic extract. The methanolic and ethyl acetate extracts can be formulated as tissanes and extracts as health supplements as a prophylaxis measure for non-communicable diseases pending further toxicological investigations.

Enterobacter hormaechei-Driven Novel Biosynthesis of Tin Oxide Nanoparticles and Evaluation of Their Anti-aging, Cytotoxic, and Enzyme Inhibition Potential.

Nanotechnology is a research hotspot that has gained considerable interest due to its potential inferences in the bioscience, medical, and engineering disciplines. The present study uses biomass from the Enterobacter hormaechei EAF63 strain to create bio-inspired metallic tin oxide nanoparticles (SnO2 NPs). The biosynthesized NPs were extensively analyzed using UV spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and Fourier transform infrared (FTIR) techniques. The identification of the crystalline phase was confirmed by XRD. The SEM technique elucidated the morphological characteristics and size of SnO2 NPs. SEM investigation revealed that the SnO2 NPs have a size of 10 nm with spherical morphology. The capping of NPs was confirmed by FTIR analysis that revealed the presence of different compounds found in the biomass of the E. hormaechei EAF63 strain. Later, EDX confirmed the elemental composition of NPs. Moreover, the synthesized SnO2 NPs were employed for important applications including anti-aging, anti-Alzheimer's, anti-inflammatory, anti-larvicidal, and antibacterial action against sinusitis pathogens. The highest value was observed for Streptococcus pyogenes (19.75 ± 0.46), followed by Moraxella catarrhalis (17.49 ± 0.82) and Haemophilus influenzae (15.31 ± 0.73), respectively. Among the used concentrations, the highest inhibition of 76.8 ± 0.93 for 15-lipoxygenase (15-LOX) was observed at 400 μg/mL, followed by 67.4 ± 0.91 for cyclooxygenase-1 (COX-1). So, as an outcome, E. hormaechei-mediated SnO2 NPs might be considered as the safe and effective nanoplatforms for multifunctional biological applications in the field of nanomedicine.

Screening and molecular dynamics simulation of compounds inhibiting MurB enzyme of drug-resistant Mycobacterium tuberculosis: An in-silico approach

Mycobacterium tuberculosis (MTB) is becoming more and more resistant to drugs and it is a common problem, making current antimicrobials ineffective and highlighting the need for new TB drugs. One of the promising targets for treating MTB is MurB enzymes. This study aimed to identify potential inhibitors of MurB enzymes in M. tuberculosis, as drug resistance among MTB is a significant problem. Attempts are being made to conduct a virtual screening of 30,417 compounds, and thirty-two compounds were chosen for further analysis based on their binding conformations. The selected compounds were assessed for their drug-likeness, pharmacokinetics, and physiochemical characteristics, and seven compounds with binding energy lower than flavin (FAD) were identified. Further, molecular dynamics simulation analysis of these seven compounds found that four of them, namely DB12983, DB15688, ZINC084726167, and ZINC254071113 formed stable complexes with the MurB binding site, exhibiting promising inhibitory activity. These compounds have not been mentioned in any other study, indicating their novelty. The study suggests that these four compounds could be promising candidates for treating MTB, but their effectiveness needs to be validated through in vitro and in vivo experiments. Overall, the findings of this study provide new insight into potential drug targets and candidates for combating drug-resistant MTB.

Synthesis and evaluation of anti-inflammatory and anti-nociceptive potentials of biopolymer based curcumin nanoparticle construct: In silico, in vitro and in vivo studies

The present study focused on the synthesis and characterization of curcumin nanoparticles (GKCNP) using a biopolymer Gum kondagogu, which acts as reducing, stabilizing and capping agent. The synthesized GKCNP are well dispersed, circular in shape with a size of 95 ± 20 nm and exhibited enhanced drug release profile. Further, the anti-inflammatory potentials of GKCNP and curcumin were carried out in in silico, in vitro and in vivo studies. Diclofenac was used as a reference standard for comparison.The in-silico studies emphasizing that curcumin exhibited highest binding score of -9.2 kcal mol-1 against COX-2 protein but not COX-1, demonstrating the anti-inflammatory activity may be due to inhibition of COX-2 enzyme. Therefore, the in vitro studies were carried out against COX-2 enzyme specifically. For GKCNP, the percent inhibition of COX-2 enzyme were found to be 89% whereas, for curcumin and diclofenac as 62 and 85%, signifyingcurcumin in nanoform acts as a potent COX-2 enzyme inhibitor when compared to pure curcumin.The carrageenan induced paw edema and tail flick assessments revealed that the test compounds GKCNP, curcumin and diclofenac exhibited reduction of edema in a linear pattern in second phase, confirming that the mechanism of actioninvolves reduction of prostaglandins through inhibition of cyclooxygenase2.

Chemical characterization and biological abilities of Anthocleista djalonensis collected from two locations of Ivory Coast

AbstractIn this study, the total phenolic and flavonoid contents, HPLC‐DAD detected phytochemicals, antioxidant and enzyme inhibitory potential of methanolic and aqueous (as infusion) extracts of the medicinal plant, Anthocleista djalonensis (leaf and stem bark) collected from two locations, Mafiblé and Prikro, in Ivory Coast, were investigated. The ranges of total phenolic and flavonoid contents obtained were 14.17–46.95 mg gallic acid equivalent (GAE)/g and 2.96–34.76 mg rutin equivalent (RE)/g, respectively. Antioxidant abilities in terms of radical scavenging, reducing and metal chelating activity of the extracts in different assays were as follows: DPPH (4.90–48.82 mg trolox equivalent [TE]/g), ABTS (21.05–81.89 mg TE/g), CUPRAC (29.54–122.33 mg TE/g), FRAP (17.53–94.06 mg TE/g) and metal chelating (10.09–28.49 mg EDTAE/g. The extracts of A. djalonensis collected from Mafiblé, especially those of stem bark, contained higher level of total bioactive contents compared to Prikro extracts, detected by high‐performance liquid chromatography with photodiode‐array detection (HPLC‐DAD). Only the methanolic extracts irrespective of plant parts/location, showed inhibition against acetylcholinesterase (1.42–2.12 mg galantamine equivalent (GALAE)/g), while only the stem bark methanolic extract of A. djalonensis from Mafiblé was found to inhibit butyrylcholinesterase (0.65 mg GALAE/g). Thus, findings from this study could be useful for better application of the medicinal benefits from this plant.

Impact of Harvest Month and Drying Process on the Nutritional and Bioactive Properties of Wild Palmaria palmata from Atlantic Canada.

The macroalga Palmaria palmata could be a sustainable and nutritional food resource. However, its composition may vary according to its environment and to processing methods used. To investigate these variations, wild P. palmata from Quebec were harvested in October 2019 and June 2020, and dried (40 °C, ≃5 h) or stored as frozen controls (-80 °C). The chemical (lipids, proteins, ash, carbohydrates, fibers), mineral (I, K, Na, Ca, Mg, Fe), potential bioactive compound (carotenoids, polyphenols, β-carotene, α-tocopherol) compositions, and the in vitro antioxidant activity and angiotensin-converting enzyme (ACE) inhibition potential of water-soluble extracts were determined. The results suggested a more favorable macroalgae composition in June with a higher content of most nutrients, minerals, and bioactive compounds. October specimens were richer only in carbohydrates and carotenoids. No significant differences in antioxidant or anti-ACE inhibitory activities were found between the two harvest months. The drying process did not significantly impact the chemical and mineral compositions, resulting in only small variations. However, drying had negative impacts on polyphenols and anti-ACE activities in June, and on carotenoids in October. In addition, a concentration effect was observed for carotenoids, β-carotene and α-tocopherol in June. To provide macroalgae of the highest nutritional quality, the drying process for June specimens should be selected.

In-vitro high-throughput library screening-Kinetics and molecular docking studies of potent inhibitors of α-glucosidase.

High throughput screening of synthetic compounds against vital enzymes is the way forward for the determination of potent enzyme inhibitors. In-vitro high throughput library screening of 258 synthetic compounds (comp. 1-258), was performed against α-glucosidase. The active compounds out of this library were investigated for their mode of inhibition and binding affinities towards α-glucosidase through kinetics as well as molecular docking studies. Out of all the compounds selected for this study, 63 compounds were found active within the IC50 range of 3.2 μM to 50.0 μM. The most potent inhibitor of α-glucosidase out of this library was the derivative of an oxadiazole (comp. 25). It showed the IC50 value of 3.23 ± 0.8 μM. Other highly active compounds were the derivatives of ethyl-thio benzimidazolyl acetohydrazide with IC50 values of 6.1 ± 0.5 μM (comp. 228), 6.84 ± 1.3 μM (comp. 212), 7.34 ± 0.3 μM (comp. 230) and 8.93 ± 1.0 μM (comp. 210). For comparison, the standard (acarbose) showed IC50 = 378.2 ± 0.12 μM. Kinetic studies of oxadiazole (comp. 25) and ethylthio benzimidazolyl acetohydrazide (comp. 228) derivatives indicated that Vmax and Km, both change with changing concentrations of inhibitors which suggests an un-competitive mode of inhibition. Molecular docking studies of these derivatives with the active site of α-glucosidase (PDB ID:1XSK), revealed that these compounds mostly interact with acidic or basic amino acid residues through conventional hydrogen bonds along with other hydrophobic interactions. The binding energy values of compounds 25, 228, and 212 were -5.6, -8.7 and -5.4 kcal.mol-1 whereas RMSD values were 0.6, 2.0, and 1.7 Å, respectively. For comparison, the co-crystallized ligand showed a binding energy value of -6.6 kcal.mol-1 along with an RMSD value of 1.1 Å. Our study predicted several series of compounds as active inhibitors of α-glucosidase including some highly potent inhibitors.

Discovery of Potent Angiotensin-Converting Enzyme Inhibitors in Pomegranate as a Treatment for Hypertension.

Pomegranate (Punica granatum L.) is associated with numerous health benefits due to its high levels of antioxidant polyphenolic substances. Since pomegranate extract has been shown to inhibit angiotensin-converting enzyme (ACE), the potential inhibitory effect of most of its main constituents against ACE is unknown. Therefore, we tested the activities of 24 major compounds, the majority of which significantly inhibited ACE. Notably, pedunculagin, punicalin, and gallagic acid were the most effective ACE inhibitors with IC50 values of 0.91, 1.12, and 1.77 μM, respectively. As demonstrated in molecular docking studies, compounds block ACE by forming multiple hydrogen bonds and hydrophobic interactions with catalytic residues and zinc ions in ACE's C- and N-domains, consequently inhibiting ACE's catalytic activity. Also, the most active pedunculagin stimulated nitric oxide (NO) production, activated the endothelial nitric oxide synthase enzyme (eNOS), and significantly increased eNOS protein expression levels up to 5.3-fold in EA.hy926 cells. Furthermore, pedunculagin increased in cellular calcium (Ca2+) concentration promoted eNOS enzyme activation and reduced the production of reactive oxygen species (ROS). In addition, the active compounds improved glucose uptake in insulin-resistant C2C12 skeletal muscle cells in a dose-dependent manner. The results of these computational, in vitro, and cellular experiments provide further evidence to the traditional medicine that involves using pomegranates to treat cardiovascular diseases like hypertension.

Inhibitory effects of methanolic extracts from the stem barks of ten Mexican Bursera Jacq. ex L. species on the activity of α-amylase and acetylcholinesterase from Tenebrio molitor

Methanolic stem bark extracts from ten Mexican Bursera Jacq. ex L. species were evaluated in vitro with regard to their inhibitory activity against two Tenebrio molitor-derived enzymes. Seven extracts (B. bicolor, B. copallifera, B. fagaroides, B. grandifolia, B. lancifolia, B. linanoe, and B. longipes) reduced α-amylase activity by 55.37% to 96.25%, with three samples proving to be particularly potent α-amylase inhibitors (B. grandifolia, B. lancifolia, and B. linanoe; IC50 = 162, 132, and 186 µg/mL, respectively). In contrast, no extract inhibited acetylcholinesterase activity by more than 39.94%. Quantitative HPLC analysis did not reveal any clear correlation between the species-specific flavonoid or phenolic acid profiles and the respective extracts’ enzyme inhibitory activity. The findings reported herein do not only contribute to improving the current state of knowledge regarding the enzyme inhibitory potential of the Bursera genus, but could also lead to the development of new sustainable bioinsecticides.

Determination of antioxidant, DNA protection, enzyme inhibition potential and molecular docking studies of a biomarker ursolic acid in Nepeta species

Ursolic acid (UA), which has many biological properties such as anti-cancer, anti-inflammatory and antioxidant, and regulates some pharmacological processes, has been isolated from the flowers, leaves, berries and fruits of many plant species. In this work, UA was purified from the methanol-chloroform crude extract of Nepeta species (N. aristata, N. baytopii, N. italica, N. trachonitica, N. stenantha) using a silica gel column with chloroform or ethyl acetate solvents via bioactivity-guided isolation. The most active sub-fractions were determined under bioactivities using antioxidant and DNA protection activities and enzyme inhibitions. UA was purified from these fractions and its structure was elucidated by NMR spectroscopy techniques. The highest amount of UA was found in N. stenantha (8.53 mg UA/g), while the lowest amount of UA was found in N. trachonitica (1.92 mg UA/g). The bioactivities of UA were evaluated with antioxidant and DNA protection activities, enzyme inhibitions, kinetics and interactions. The inhibition values (IC50) of α-amylase, α-glucosidase, urease, CA, tyrosinase, lipase, AChE, and BChE were determined between 5.08 and 181.96 µM. In contrast, Ki values of enzyme inhibition kinetics were observed between 0.04 and 0.20 mM. In addition, Ki values of these enzymes for enzyme-UA interactions were calculated as 0.38, 0.86, 0.45, 1.01, 0.23, 0.41, 0.01 and 2.24 µM, respectively. It is supported that UA can be widely used as a good antioxidant against oxidative damage, an effective DNA protector against genetic diseases, and a suitable inhibitor for metabolizing enzymes. Communicated by Ramaswamy H. Sarma

An investigation on photocatalytic and α-amylase inhibitory activities of Co(II) and Zn(II) phthalocyanines

Metallophthalocyanines have broad range of photocatalytic and biological applications, so they have been investigated widely by the scientific community. In this study, P4P-1 and P4P-2 phthalocyanines and their water soluble derivatives (QP4P-1 and QP4P-2) were synthesized and characterized by different spectral data. Photocatalytic performance of QP4P-1 and QP4P-2 were tested on photodegradation of 4-nitrophenol (4-NP). QP4P-1 shows remarkable photocatalytic activity with 90 % product conversion (TON:1500) in aqueous solution of 4-nitrophenol. α-amylase inhibition assay is performed in order to find out the enzyme inhibitory potential of water soluble phthalocyanine QP4P-2. QP4P-2 inhibited α-amylase 64.2 ± 0.8 % at 300 µM concentration and the IC50values ​​of the molecule was calculated as 128.2 ± 1.5 µM. QP4P-2 reflects the potential α-amylase inhibitory activity as compared to others.

Halting aberrant DNA methylation via in silico Identification of potent inhibitors of DNMT3B enzyme: Atomistic insights

To date, Cancer remains a global threat due to its impact on growing life expectancy. With the many efforts and methods of combating the disease, complete success remains a challenge owing to several limitations including cancer cells developing resistance through mutations, off-target effect of some cancer drugs resulting in toxicities, among many others. Aberrant DNA methylation is understood to be the primary reason for improper gene silence, which can result in neoplastic transformation, carcinogenesis, and tumour progression. DNA methyltransferase B (DNMT3B) enzyme is considered a potential target for the treatment of several cancers due to its important role in DNA methylation. However, only a few DNMT3B inhibitors have been reported to date. Herein, in silico molecular recognition techniques such as Molecular docking, Pharmacophore-based virtual screen and MD simulation were employed to identify potential inhibitors of DNMT3B that can halt aberrancy in DNA methylation. Findings initially identified 878 hit compounds based on a designed pharmacophore model from the reference compound Hypericin. Molecular docking was used to rank the hits by testing their efficiency when bound to the target enzyme and the top three (3) selected. All three (3) of the top hits showed excellent pharmacokinetic properties but two (2) (Zinc33330198 and Zinc77235130) were identified to be non-toxic. Molecular dynamic simulation of the final two hits showed good stability, flexibility, and structural rigidity of the compounds on DNMT3B. Finally, thermodynamic energy estimations show both compounds had favourable free energies comprising − 26.04 kcal/mol for Zinc77235130 and − 15.73 kcal/mol for Zinc33330198. Amongst the final two hits, Zinc77235130 showed consistency in favourable results across all the tested parameters and was thus selected as the lead compound for further experimental validation. The identification of this lead compound will form important basis for the inhibition of aberrant DNA methylation in cancer therapy.

Preparation, characterization, antioxidant activity of 1-(2-furoyl) thiourea derivatives and study the molecular docking of them as potent inhibitors of Urease enzyme

In this work, we synthesized thirteen compounds of 1-(2-furoyl)thiourea derivatives 1-13 by conversion of 2-furoyl chloride to 2-furoyl isothiocyanate by reacting it with potassium thiocyanate in dry acetone in a quite short reflux time then, in the same pot, different of (primary and secondary amines) were added individually to achieve thiourea derivatives. The products were characterized spectroscopically using (FT-IR, 1H NMR and 13C NMR) techniques. Some of them were evaluated as antioxidant agents using DPPH radical scavenging method, and all were examined theoretically as enzyme inhibitors against Bacillus pasteurii urease (pdb id: 4ubp) and by studying molecular docking using Autodock (4.2.6) software.

Roflumilast ameliorates diabetic nephropathy in rats through down-regulation of JAK/STAT signaling pathway.

Roflumilast is a potent selective inhibitor of the phosphodiesterase-4 enzyme which greatly manifest an anti-inflammatory activity in chronic obstructive pulmonary patients. Inflammation is a prominent factor in the prevalence of diabetic nephropathy, one of the most prevalent microvascular complications of Diabetes Mellitus. The present study was undertaken to assess the potential role of roflumilast in diabetic nephropathy. The model was developed by feeding a high-fat diet for four weeks and following streptozotocin (30mg/kg) injection intraperitoneally. The rats with > 13.8mmol/L blood glucose were treated with roflumilast (0.25, 0.5, 1mg/kg) and standard metformin (100mg/kg) orally once a day for eight weeks. Roflumilast (1mg/kg) remarkably improved renal damage, indicated by an increase in 16% albumin, a decrease in 5% serum creatinine, 12% BUN, 19% HbA1c, and 34% blood glucose. It also significantly improves the oxidative stress levels, which was indicated by a decrease in 18% MDA level and an increase in GSH, SOD, and catalase by 6%, 4%, and 5%, respectively. In addition, Roflumilast (1mg/kg) decreased the HOMA-IR index by 28% and increased the pancreatic β-cells functioning by 30%. Moreover, significant improvement in histopathological abnormalities were observed in roflumilast treatment groups. Roflumilast treatment was shown to down-regulate the gene expressions of TNF-α (2.1-fold), NF-kB (2.3-fold), MCP-1 (2.5-fold), fibronectin (2.7-fold), collagen IV (2.7-fold), STAT 1(1.06-fold), and STAT 3 (1.20-fold) and upregulated the expression of the Nrf2 (1.43-fold) gene. Roflumilast manifested a potential role in diabetic nephropathy as a renoprotective agent. Roflumilast effectively down-regulates the JAK/STAT pathway and restores renal functions.

Synthesis and Molecular Docking Studies of Novel Biheterocyclic Propanamides as Antidiabetic Agents Having Mild Cytotoxicity.

The aim of this work was to bring forth some new hybrid molecules having pharmacologically potent indole and 1,3,4-oxadiazole heterocyclic moieties unified with a propanamide entity. The synthetic methodology was initiated by esterification of 2-(1H-indol-3-yl)acetic acid (1) in a catalytic amount of sulfuric acid and ethanol in excess, to form ethyl 2-(1H-indol-3-yl)acetate (2), which was converted to 2-(1H-indol-3-yl)acetohydrazide (3) and further transformed to 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). 3-Bromopropanoyl chloride (5) was reacted with various amines (6a-s) in aqueous alkaline medium to generate a series of electrophiles, 3-bromo-N-(substituted)propanamides (7a-s), and these were further reacted with nucleophile 4 in DMF and NaH base to yield the targeted N-(substituted)-3-{(5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl)sulfanyl}propanamides (8a-s). The chemical structures of these biheterocyclic propanamides were confirmed by IR, 1H NMR, 13C NMR, and EI-MS spectral techniques. These compounds were evaluated for their enzyme inhibitory potentials against the α-glucosidase enzyme, where the compound 8l showed promising enzyme inhibitory potential with an IC50 value less than that of the standard acarbose. Molecular docking results of these molecules were coherent with the results of their enzyme inhibitory potentials. Cytotoxicity was assessed by the percentage of hemolytic activity method, and these compounds generally exhibited very low values as compared to the reference standard, Triton-X. Hence, some of these biheterocyclic propanamides might be considered as salient therapeutic agents in further stages of antidiabetic drug development.