Natural product-inspired [3 + 2] cycloaddition-based spirooxindoles as dual anticancer agents: synthesis, characterization, and biological evaluation by in vitro and in silico methods.

Breast and colorectal cancers are the most common tumors, with high recurrence and low survival rates. We designed and synthesized a series of spirooxindole pyrrolidinyl derivatives, which were further evaluated for anti-proliferative activity using MDA-MB-468 and HCT 15 cell lines. The best inhibitor of this class, compound 6f, showed a very good inhibition potency, both on the MDA-MB-468 and HCT 15 cells as confirmed by molecular docking and molecular dynamic studies that predicted its binding mode into the active site of the targets. In summary, this study provided a new anti-proliferative derivative 6f which is worthy of further research.

From sugar binders to diabetes fighters: the lectin saga of antihyperglycemic activity through systematic review and meta-analysis.

Introduction: Lectins are carbohydrate-binding proteins that are extremely selective for sugar groups in the other molecules. As a result, they perform a variety of roles in biological processes involving cell, carbohydrate, and protein recognition at the cellular and molecular levels. Because lectins can bind to carbohydrates, they may play a role in determining the rate of carbohydrate digestion. They also bind to some proteins involved in diabetes mellitus (DM) pathophysiology. The present review aims to summarize the efficiency of lectins from different sources as potential antihyperglycemic agents. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were employed for the drafting. In this regard, published scientific articles on the effects of different lectins on blood glucose (BG), glucose tolerance, hormonal effects, carbohydrate-digesting enzymes, oxidative stress, and insulin production process were collected from reputed journals using electronic databases. Furthermore, the toxicity effects of lectins from different sources were collected. A specific keyword search was completed to collect numerous articles with unique experimental designs and significant results. This was followed by the selection of the requisite articles based on the criteria designed by the authors. Data extraction was based on the common research elements included in the articles. Results and Discussion: Of 13 identified studies, 11 studies were considered after double screening based on the inclusion criteria. All 11 pharmacological investigations were considered for review. Subsequent studies reflected on the pharmacological properties of lectins on the levels of BG, oxidative stress, ß-cell proliferation, insulin resistance, inhibition of carbohydrate digesting enzymes, body weight, food and water intake, lipid profile, and other parameters. This review highlights lectins as potential anti-diabetic agents. Conclusion: However, due to limited research, systematic evaluation is recommended for their development and promotion as effective potential antihyperglycemic agents. The clinical efficacy and safety of lectins against diabetes mellitus must also be evaluated.

Characterization of Lactobacillus spp. as Probiotic and Antidiabetic Potential Isolated from Boza, Traditional Fermented Beverage in Turkey.

Boza, a cereal-based beverage popular in southeast Europe, is fortified with probiotics and is believed to positively impact the composition of the gut microflora. This investigation focused on fermented cereal-based beverage boza to identify strains of probiotic Lactobacillus spp. capable of inhibiting carbohydrate-hydrolysing enzymes α-glucosidase (AG) and α-amylase (AA). The isolated bacterial strains underwent a comprehensive assessment, including biochemical, molecular, and probiotic trait analyses such as tolerance survivability, adhesion, safety, and health-promoting attributes. We evaluated the inhibitory potential of the supernatant, cell lysate, and intact cells of Lactobacillus spp. Molecular analysis has revealed that isolates RAMULAB30 and RAMULAB29 exhibit a significant genetic similarity (>97%) to Lacticaseibacillus paracasei and Limosilactobacillus fermentum, respectively. These findings are documented in the NCBI database. They exhibited significant resistance to gastrointestinal and intestinal fluids, also indicating their potential for adhesion. Additionally, the isolates showed a significant antibacterial activity, particularly against Micrococcus luteus. They showed resistance to vancomycin and methicillin antibiotics but were more susceptible to streptomycin and ampicillin. Furthermore, the strains demonstrated antioxidant properties. To ensure their safety, a haemolytic assay was conducted despite their general recognition as safe (GRAS) status. The study primarily aimed to evaluate the inhibitory effects of the extract on enzymes AG and AA. Bacterial isolates demonstrated a significant inhibitory activity against both enzyme AG (32%-67% inhibition) and enzyme AA (18%-46% inhibition) in different forms, including supernatant (CS), lysed extract (CE), and intact cell (IC). These findings underscore the potential of bacterial isolates to inhibit the enzyme activity effectively. Furthermore, the L. fermentum RAMULAB29 and L. paracasei RAMULAB30 strains exhibit remarkable antidiabetic potential. Food products incorporating these strains have promising prospects as nutraceuticals, providing improved health benefits.

Synthesis, molecular docking, analgesic, anti-inflammatory, and ulcerogenic evaluation of thiophene-pyrazole candidates as COX, 5-LOX, and TNF-α inhibitors.

The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities followed by the in vivo analgesic, anti-inflammatory, and ulcerogenic evaluations. The synthesized series (7a-j) were characterized using 1H NMR, 13C NMR, FT-IR, and mass spectral analysis. Initially, the compounds (7a-j) were evaluated for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities and the compound (7f) with two phenyl substituents in the pyrazole ring and chloro substituent in the thiophene ring and the compound (7g) with two phenyl substituents in the pyrazole ring and bromo substituent in the thiophene ring were observed as potent compounds among the series. The compounds (7f and 7g) with effective in vitro potentials were further analyzed for analgesic, anti-inflammatory, and ulcerogenic evaluations. Also, to ascertain the binding affinities of compounds (7a-j), docking assessments were carried out and the ligand (7f) with the highest binding affinity was docked to know the interactions of the ligand with amino acids of target proteins.

Investigating the antidiabetic efficacy of dairy-derived Lacticaseibacillus paracasei probiotic strains: modulating α-amylase and α-glucosidase enzyme functions.

The current study aims to evaluate and characterize the probiotic andantidiabetic properties of lactic acid bacteria (LAB) obtained from milk and other dairy-based products. The strains were tested physiologically, biochemically, and molecularly. Based on biochemical tests and 16S rRNA gene amplification and sequencing, all three isolates RAMULAB18, RAMULAB19, and RAMULAB53 were identified as Lacticaseibacillus paracasei with homology similarity of more than 98%. The inhibitory potential of each isolate against carbohydrate hydrolysis enzymes (α-amylase and α-glucosidase) was assessed using three different preparations of RAMULAB (RL) isolates: the supernatant (RL-CS), intact cells (RL-IC), and cell-free extraction (RL-CE). Additionally, the isolate was evaluated for its antioxidant activity against free radicals (DPPH and ABTS). The strain's RL-CS, RL-CE, and RL-IC inhibited α-amylase (17.25 to 55.42%), α-glucosidase (15.08-59.55%), DPPH (56.42-87.45%), and ABTS (46.35-78.45%) enzymes differently. With the highest survival rate (>98%) toward tolerance to gastrointestinal conditions, hydrophobicity (>42.18%), aggregation (>74.21%), as well as attachment to an individual's colorectal cancer cell line (HT-29) (>64.98%), human buccal and chicken crop epithelial cells, all three isolates exhibited extensive results. All three isolates exhibited high resistance toward antibiotics (methicillin, kanamycin, cefixime, and vancomycin), and other assays such as antibacterial, DNase, hemolytic, and gelatinase were performed for safety assessment. Results suggest that the LAB described are valuable candidates for their significant health benefits and that they can also be utilized as a beginning or bio-preservative tradition in the food, agriculture, and pharmaceutical sectors. The LAB isolates are excellent in vitro probiotic applicants and yet additional in vivo testing is required.

An insight into the cytotoxic, antimicrobial, antioxidant, and biocontrol perspective of novel Iron(III) complexes of substituted benzimidazoles: Inhibition kinetics and molecular simulations.

Mononuclear complexes [FeCl3L2(OH2)] (L = L1, L2) were designed and synthesized by combining FeCl3 with 2-(3'-Aminophenylbenzimidazole) (L1) and 2-[(3'-N-Salicylidinephenyl)benzimidazole] (L2) and were characterized by physico-analytical strategies. The redox properties of the complexes were disclosed by the cyclic voltammetric method. Further, the interactions of complexes with proteins were studied by performing molecular docking engaging protein models of common cancer therapeutic targets to foresee their affinity to bind to these proteins. The complexes evidenced better protein-ligand docking (-8.4 and -9.0 kcal mol-1) and higher binding energies than their ligands. However, the L1 complex displayed improved binding free energy (-33.576 ± 1.01 kcal mol-1) compared to the other complexes and individual ligands. These compounds were screened for in vitro cytotoxic assays against triple-negative breast cancer cell lines (MDA-MB-468 cells), anti-inflammatory, antimicrobial, and antioxidant properties. The in vitro study complemented the in silico assay; therefore, these compounds may be a viable choice for expanding anticancer therapy. Additionally, the L2 showed better biocontrol activity owing to the enhanced growth of Trichoderma and inhibited the growth of Fusarium oxysporum.Communicated by Ramaswamy H. Sarma.

Protocol to identify multiple protein targets and therapeutic compounds using an in silico polypharmacological approach.

Polypharmacology aids in the identification of multiple protein targets involved in disease pathology and selecting appropriate therapeutic compounds interacting with protein targets. Here, we present a protocol to identify the targets involved in obesity-linked diabetes and suitable phytocompounds to bind with the identified target. We describe steps to install and use softwares for identifying several protein targets by linking multiple diseases. This protocol allows the use of therapeutic compounds of both phytochemical and synthetic origins. For complete details on the use and execution of this protocol, please refer to Martiz et al.,1 and Maradesha et al.2.

Screening for potential novel probiotic Levilactobacillus brevis RAMULAB52 with antihyperglycemic property from fermented Carica papaya L.

Probiotics are live microorganisms with various health benefits when consumed in appropriate amounts. Fermented foods are a rich source of these beneficial organisms. This study aimed to investigate the probiotic potential of lactic acid bacteria (LAB) isolated from fermented papaya (Carica papaya L.) through in vitro methods. The LAB strains were thoroughly characterized, considering their morphological, physiological, fermentative, biochemical, and molecular properties. The LAB strain's adherence and resistance to gastrointestinal conditions, as well as its antibacterial and antioxidant capabilities, were examined. Moreover, the strains were tested for susceptibility against specific antibiotics, and safety evaluations encompassed the hemolytic assay and DNase activity. The supernatant of the LAB isolate underwent organic acid profiling (LCMS). The primary objective of this study was to assess the inhibitory activity of α-amylase and α-glucosidase enzymes, both in vitro and in silico. Gram-positive strains that were catalase-negative and carbohydrate fermenting were selected for further analysis. The LAB isolate exhibited resistance to acid bile (0.3% and 1%), phenol (0.1% and 0.4%), and simulated gastrointestinal juice (pH 3-8). It demonstrated potent antibacterial and antioxidant abilities and resistance to kanamycin, vancomycin, and methicillin. The LAB strain showed autoaggregation (83%) and adhesion to chicken crop epithelial cells, buccal epithelial cells, and HT-29 cells. Safety assessments indicated no evidence of hemolysis or DNA degradation, confirming the safety of the LAB isolates. The isolate's identity was confirmed using the 16S rRNA sequence. The LAB strain Levilactobacillus brevis RAMULAB52, derived from fermented papaya, exhibited promising probiotic properties. Moreover, the isolate demonstrated significant inhibition of α-amylase (86.97%) and α-glucosidase (75.87%) enzymes. In silico studies uncovered that hydroxycitric acid, one of the organic acids derived from the isolate, interacted with crucial amino acid residues of the target enzymes. Specifically, hydroxycitric acid formed hydrogen bonds with key amino acid residues, such as GLU233 and ASP197 in α-amylase, and ASN241, ARG312, GLU304, SER308, HIS279, PRO309, and PHE311 in α-glucosidase. In conclusion, Levilactobacillus brevis RAMULAB52, isolated from fermented papaya, possesses promising probiotic properties and exhibits potential as an effective remedy for diabetes. Its resistance to gastrointestinal conditions, antibacterial and antioxidant abilities, adhesion to different cell types, and significant inhibition of target enzymes make it a valuable candidate for further research and potential application in the field of probiotics and diabetes management.

Inhibition of carbohydrate hydrolyzing enzymes by a potential probiotic Levilactobacillus brevis RAMULAB49 isolated from fermented Ananas comosus.

The research aimed to explore the potential probiotic characteristics of Levilactobacillus brevis RAMULAB49, a strain of lactic acid bacteria (LAB) isolated from fermented pineapple, specifically focusing on its antidiabetic effects. The importance of probiotics in maintaining a balanced gut microbiota and supporting human physiology and metabolism motivated this research. All collected isolates underwent microscopic and biochemical screenings, and those exhibiting Gram-positive characteristics, negative catalase activity, phenol tolerance, gastrointestinal conditions, and adhesion capabilities were selected. Antibiotic susceptibility was assessed, along with safety evaluations encompassing hemolytic and DNase enzyme activity tests. The isolate's antioxidant activity and its ability to inhibit carbohydrate hydrolyzing enzymes were examined. Additionally, organic acid profiling (LC-MS) and in silico studies were conducted on the tested extracts. Levilactobacillus brevis RAMULAB49 demonstrated desired characteristics such as Gram-positive, negative catalase activity, phenol tolerance, gastrointestinal conditions, hydrophobicity (65.71%), and autoaggregation (77.76%). Coaggregation activity against Micrococcus luteus, Pseudomonas aeruginosa, and Salmonella enterica serovar Typhimurium was observed. Molecular characterization revealed significant antioxidant activity in Levilactobacillus brevis RAMULAB49, with ABTS and DPPH inhibition rates of 74.85% and 60.51%, respectively, at a bacterial cell concentration of 109 CFU/mL. The cell-free supernatant exhibited substantial inhibition of α-amylase (56.19%) and α-glucosidase (55.69%) in vitro. In silico studies supported these findings, highlighting the inhibitory effects of specific organic acids such as citric acid, hydroxycitric acid, and malic acid, which displayed higher Pa values compared to other compounds. These outcomes underscore the promising antidiabetic potential of Levilactobacillus brevis RAMULAB49, isolated from fermented pineapple. Its probiotic properties, including antimicrobial activity, autoaggregation, and gastrointestinal conditions, contribute to its potential therapeutic application. The inhibitory effects on α-amylase and α-glucosidase activities further support its anti-diabetic properties. In silico analysis identified specific organic acids that may contribute to the observed antidiabetic effects. Levilactobacillus brevis RAMULAB49, as a probiotic isolate derived from fermented pineapple, holds promise as an agent for managing diabetes. Further investigations should focus on evaluating its efficacy and safety in vivo to consider its potential therapeutic application in diabetes management.

Bioactive profiling and evaluation of anti-proliferative and anti-cancerous properties of Shivagutika, an Indian polyherbal formulation synchronizing in vitro and in silico approaches.

Shivagutika is a polyherbal formulation mentioned in Ayurveda, the oldest system of medicine. The aim of this study was to investigate the anti-breast cancer potential of DCM extract of Shivagutika using MCF-7, MDA-MB-231, and MDA-MB-468. Primarily, various extracts of Shivagutika were prepared and subjected to primary in vitro analysis-total protein, phenolic acid content, and flavonoid content. DCM extract among all the extracts showed the promising results hence, it was subjected to LC-MS/MS analysis to identify the phytochemicals. The same extract was subjected to anti-proliferation assay and anti-cancer assay. It inhibited all the 3 cell lines and increased the activity of Caspase 3, pro-apoptotic protein. Further, to find the potent molecule(s) in silico analysis (molecular docking and molecular dynamics simulation studies) was performed. Sciadopitysin was identified as a potent molecule among all phytochemicals as it interacted with Caspase 3 with a binding energy of -7.2 kcal/mol. MD simulation studies also revealed that Sciadopitysin was stable inside the binding pocket of Caspase 3 by interacting with the amino acids in the catalytic site thereby activating the Caspase 3 levels. By all the above results, Shivagutika could be used as a potent anti-breast cancer agent (specifically DCM extract of Shivagutika) which could decrease the cases of breast cancer in future.

Antidiabetic Activity of Potential Probiotics Limosilactobacillus spp., Levilactobacillus spp., and Lacticaseibacillus spp. Isolated from Fermented Sugarcane Juice: A Comprehensive In Vitro and In Silico Study.

Probiotics are regarded as a potential source of functional foods for improving the microbiota in human gut. When consumed, these bacteria can control the metabolism of biomolecules, which has numerous positive effects on health. Our objective was to identify a probiotic putative Lactobacillus spp. from fermented sugarcane juice that can prevent α-glucosidase and α-amylase from hydrolyzing carbohydrates. Isolates from fermented sugarcane juice were subjected to biochemical, molecular characterization (16S rRNA) and assessed for probiotic traits. Cell-free supernatant (CS) and extract (CE) and also intact cells (IC) were examined for the inhibitory effect on α-glucosidase and α-amylase. CS of the strain showed the highest inhibition and was subjected to a liquid chromatography-mass spectrometry (LCMS) analysis to determine the organic acid profile. The in silico approach was employed to assess organic acid stability and comprehend enzyme inhibitors' impact. Nine isolates were retained for further investigation based on the preliminary biochemical evaluation. Limosilactobacillus spp., Levilactobacillus spp., and Lacticaseibacillus spp. were identified based on similarity > 95% in homology search (NCBI database). The strains had a higher survival rate (>98%) than gastric and intestinal fluids, also a high capacity for adhesion (hydrophobicity > 56%; aggregation > 80%; HT-29 cells > 54%; buccal epithelial cells > 54%). The hemolytic assay indicated that the isolates could be considered safe. The isolates' derivatives inhibited enzymes to varying degrees, with α-glucosidase inhibition ranging from 21 to 85% and α-amylase inhibition from 18 to 75%, respectively. The CS of RAMULAB54 was profiled for organic acid that showed the abundance of hydroxycitric acid, citric acid, and lactic acid indicating their role in the observed inhibitory effects. The in silico approach has led us to understand that hydroxycitric acid has the ability to inhibit both the enzymes (α-glucosidase and α-amylase) effectively. Inhibiting these enzymes helps moderate postprandial hyperglycemia and regulates blood glucose levels. Due to their promising antidiabetic potential, these isolates can be used to enhance intestinal health.

α-Amylase inhibitory potential of Thunbergia mysorensis leaves extract and bioactive compounds by in vitro and computational approach.

In this study, we aim to evaluate the anti-diabetic potential of Thunbergia mysorensis leaves methanolic extract (MeL) using inhibitory assays for α-glucosidase (AG), α-amylase (AM) (carbohydrate digestive enzymes) and aldose reductase (AR) (an enzyme involved in the polyol pathway responsible for glycation). In addition to antidiabetic studies, antioxidant studies were also performed due to the fact that reactive oxygen species (ROS) are produced by various pathways under diabetic conditions. Hyperglycemia induces ROS by activating the glycation reaction and the electron transport chain in mitochondria. The MeL effectively inhibited the enzymes (AG IC50: 27.86 ± 1.0, AM IC50: 12.00 ± 0.0, AR IC50: 4.50 ± 0.09 µg/mL) and showed effective radical ion scavenging activity during the antioxidant assay (DPPH EC50: 30.10 ± 0.75, ABTS EC50: 27.25 ± 1.00, Superoxide EC50: 35.00 ± 1.50 µg/mL). Using activity-guided repeated fractionation on a silica gel column chromatography, two compounds including 3,4-dimethoxy benzoic acid (DMBA) (101 mg) and 3,4-dimethoxy cinnamic acid (DMCA) (87 mg) with potent anti-diabetic activity were extracted from the MeL of T. mysorensis leaves. Both DMBA (IC50 AG: 27.00 ± 1.05, IC50 AM: 12.15 ± 0.10, IC50 AR: 4.86 ± 0.30 µg/mL) and DMCA (IC50 AG: 27.25 ± 0.98, IC50 AM: 12.50 ± 0.20, IC50 AR: 5.00 ± 1.00 µg/mL) were subjected for enzyme inhibition. Since both compounds significantly inhibited AM, enzyme kinetics for AM inhibition was performed. The compounds also showed effective antioxidant potential (DPPH EC50: 30.50 ± 0.99, ABTS EC50: 27.86 ± 0.16, Superoxide EC50: 36.10 ± 0.24 µg/mL), and DMCA (DPPH EC50: 31.00 ± 1.00, ABTS EC50: 28.00 ± 0.25, Superoxide EC50: 36.25 ± 0.37 µg/mL). Further, to elucidate the role of DMBA and DMCA in enzyme inhibition and stability at the molecular level, both compounds were subjected for in silico enzyme inhibitory studies using molecular docking simulation, molecular dynamics (MD) simulation, and binding free energy calculations. Compared to AR and AG, AM was the most significantly inhibited enzyme (DMBA: -6.6 and DMCA: -7.8 kcal/mol), and compounds combined with AM were subjected to MD simulation. Both compounds were stable in the binding pocket of AM till 100 ns and chiefly use Van der Waal's energy to bind. Compared to the controls, both DMBA and DMCA had a higher efficiency in the inhibition of target enzymes in vitro and in silico. The presence of DMBA and DMCA is more likely to be associated with the potential of MeL in antihyperglycemic activity. This bio-computational study indicates DMBA and DMCA as potential lead inhibitors of AM and could be used as effective anti-diabetic drugs in the near future.

Computational approaches to define poncirin from Magnolia champaka leaves as a novel multi-target inhibitor of SARS-CoV-2.

Phytochemical-based drug discovery against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been the focus of the current scenario. In this context, we aimed to perform the phytochemical profiling of Magnolia champaka, an evergreen tree from the Magnoliaceae family, in order to perform a virtual screening of its phytoconstituents against different biological targets of SARS-CoV-2. The phytochemicals identified from the ethanol extract of M. champaka leaves using liquid chromatography-mass spectroscopy (LC-MS) technique were screened against SARS-CoV-2 spike glycoprotein (PDB ID: 6M0J), main protease/Mpro (PDB ID: 6LU7), and papain-like protease/PLpro (PDB ID: 7CMD) through computational tools. The experimentation design included molecular docking simulation, molecular dynamics simulation, and binding free energy calculations. Through molecular docking simulation, we identified poncirin as a common potential inhibitor of all the above-mentioned target proteins. In addition, molecular dynamics simulations, binding free energy calculations, and PCA analysis also supported the outcomes of the virtual screening. By the virtue of all the in silico results obtained, poncirin could be taken for in vitro and in vivo studies in near future.Communicated by Ramaswamy H. Sarma.

Integrated network pharmacology and molecular modeling approach for the discovery of novel potential MAPK3 inhibitors from whole green jackfruit flour targeting obesity-linked diabetes mellitus.

The current study investigates the effectiveness of phytocompounds from the whole green jackfruit flour methanol extract (JME) against obesity-linked diabetes mellitus using integrated network pharmacology and molecular modeling approach. Through network pharmacology, druglikeness and pharmacokinetics, molecular docking simulations, GO analysis, molecular dynamics simulations, and binding free energy analyses, it aims to look into the mechanism of the JME phytocompounds in the amelioration of obesity-linked diabetes mellitus. There are 15 predicted genes corresponding to the 11 oral bioactive compounds of JME. The most important of these 15 genes was MAPK3. According to the network analysis, the insulin signaling pathway has been predicted to have the strongest affinity to MAPK3 protein, which was chosen as the target. With regard to the molecular docking simulation, the greatest notable binding affinity for MAPK3 was discovered to be caffeic acid (-8.0 kJ/mol), deoxysappanone B 7,3'-dimethyl ether acetate (DBDEA) (-8.2 kJ/mol), and syringic acid (-8.5 kJ/mol). All the compounds were found to be stable inside the inhibitor binding pocket of the enzyme during molecular dynamics simulation. During binding free energy calculation, all the compounds chiefly used Van der Waal's free energy to bind with the target protein (caffeic acid: 102.296 kJ/mol, DBDEA: -104.268 kJ/mol, syringic acid: -100.171 kJ/mol). Based on these findings, it may be inferred that the reported JME phytocompounds could be used for in vitro and in vivo research, with the goal of targeting MAPK3 inhibition for the treatment of obesity-linked diabetes mellitus.

Molecular insights into the in silico discovery of corilagin from Terminalia chebula as a potential dual inhibitor of SARS-CoV-2 structural proteins.

The spike (S) glycoprotein and nucleocapsid (N) proteins are the crucial pathogenic proteins of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) virus during its interaction with the host. Even FDA-approved drugs like dexamethasone and grazoprevir are not able to curb the viral progression inside the host and are reported with adverse effects on body metabolism. In this context, we aim to report corilagin a novel, potential dual inhibitor of S and N proteins from Terminalia chebula. The bioactive compounds of T. chebula were subjected to a series of computational investigations including molecular docking simulations, molecular dynamics (MD) simulations, binding free energy calculations, and PASS pharmacological analysis. The results obtained from these studies revealed that corilagin was highly interactive with the S (-8.9 kcal/mol) and N (-9.2 kcal/mol) proteins, thereby showing dual inhibition activity. It was also found to be stable enough to induce biological activity inside the inhibitor binding pocket of the target enzymes throughout the dynamics simulation run for 100 ns. This is also confirmed by the changes in the protein conformations, evaluated using free energy landscapes. Outcomes from this investigation identify corilagin as the lead potential dual inhibitor of S and N proteins of SARS-CoV-2, which could be taken for biological studies in near future.Communicated by Ramaswamy H. Sarma.

Inhibitory effect of gallic acid from Thunbergia mysorensis against α-glucosidase, α-amylase, aldose reductase and their interaction: Inhibition kinetics and molecular simulations.

In this exploration, we assessed the antihyperglycaemic properties of methanol extract of flowers of Thunbergia mysorensis (MeT) against α-glucosidase, α-amylase and aldose reductase enzymes for the effective management of postprandial hyperglycemia. Hyperglycemia occurs when the body lacks enough insulin or is unable to correctly utilize it. MeT inhibited both the carbohydrate digestive enzymes (α-glucosidase and α-amylase) and aldose reductase, which are vital for the therapeutic control of postprandial hyperglycaemia. MeT was also found to have significant antioxidant activity. Using several spectroscopic approaches, the primary active component found in MeT was identified as gallic acid. With low Ki values, gallic acid significantly inhibited α-glucosidase (30.86 µg/mL) and α-amylase (6.50 µg/mL). Also, MeT and gallic acid both inhibited aldose reductase effectively, corresponding to an IC50 value of 3.31 and 3.05 µg/mL. Our findings imply that the presence of polyphenol compounds (identified via HPLC analysis) is more likely to be responsible for the antihyperglycaemic role exhibited by MeT via the inhibition of α-glucosidase and the polyol pathway. Further, gallic acid interacted with the key residues of the active sites of α-glucosidase (-6.4 kcal/mol), α-amylase (-5.8 kcal/mol) and aldose reductase (-5.8 kcal/mol) as observed in the protein-ligand docking. It was also predicted that gallic acid was stable inside the binding pockets of the target enzymes during molecular dynamics simulation. Overall, gallic acid derived from MeT via bioassay-guided isolation emerges as a natural antidiabetic drug and can be taken into in vivo and clinical studies shortly.Communicated by Ramaswamy H. Sarma.

Plants and endophytes - a partnership for the coumarin production through the microbial systems.

Plant-based secondary metabolite production system is well established. However, host-endophyte interaction in the production of secondary metabolite is a new less exploited area that is overcoming barriers and evolving as one of the prospective fields. Endophytes such as bacteria or fungi have the ability to produce some of the secondary metabolites that mimic the plant metabolites therefore escaping the host defence system. Coumarin is one such metabolite with immense biological functions. Most of the studies have demonstrated coumarin production from fungal endophytes but not bacterial endophytes. Herein, we present an overview of all the coumarin derivatives produced from endophytic sources and their biosynthetic pathways. Furthermore, the review also throws light on the isolation of these coumarins and different derivatives with respect to their biological activity. The biotransformation of coumarin derivatives by the action of endophytic fungi is also elaborated. The present review provides an insight on the challenges faced in the coumarin production through fungal endophytes.

Molecular docking and simulation analysis of the FimH protein with secondary metabolites from the Garcinia species.

It is of interest to document the molecular docking and simulation analysis of the FimH protein with 10 secondary metabolites from Garcinia species in the context of drug discovery for Urinary tract infections (UTIs). We report the optimal binding features of flavonoids with the FimH protein for further consideration in drug discovery.

Phyto-Computational Intervention of Diabetes Mellitus at Multiple Stages Using Isoeugenol from Ocimum tenuiflorum: A Combination of Pharmacokinetics and Molecular Modelling Approaches.

In the present study, the anti-diabetic potential of Ocimum tenuiflorum was investigated using computational techniques for α-glucosidase, α-amylase, aldose reductase, and glycation at multiple stages. It aimed to elucidate the mechanism by which phytocompounds of O. tenuiflorum treat diabetes mellitus using concepts of druglikeness and pharmacokinetics, molecular docking simulations, molecular dynamics simulations, and binding free energy studies. Isoeugenol is a phenylpropene, propenyl-substituted guaiacol found in the essential oils of plants. During molecular docking modelling, isoeugenol was found to inhibit all the target enzymes, with a higher binding efficiency than standard drugs. Furthermore, molecular dynamic experiments revealed that isoeugenol was more stable in the binding pockets than the standard drugs used. Since our aim was to discover a single lead molecule with a higher binding efficiency and stability, isoeugenol was selected. In this context, our study stands in contrast to other computational studies that report on more than one compound, making it difficult to offer further analyses. To summarize, we recommend isoeugenol as a potential widely employed lead inhibitor of α-glucosidase, α-amylase, aldose reductase, and glycation based on the results of our in silico studies, therefore revealing a novel phytocompound for the effective treatment of hyperglycemia and diabetes mellitus.

New insights on the phytochemical intervention for the treatment of neuropsychiatric disorders using the leaves of Michelia champaca: an in vivo and in silico approach.

CONTEXT: Michelia champaca L. (Magnoliaceae) has been known since ancient times for its rich medicinal properties. OBJECTIVE: The ethanol extract of Michelia champaca leaves (EEMC) was evaluated on depression and anxiety using in vivo and in silico studies. MATERIALS AND METHODS: Swiss albino mice were divided into control, standard, 100 and 200 mg/kg b.w. EEMC groups and for drug administration using oral gavage. The antidepressant activity was evaluated using forced swim test (FST) and tail suspension test (TST) whereas the anxiolytic activity through elevated plus maze and light and dark tests. The in silico studies included molecular docking against human potassium channel KCSA-FAB and human serotonin transporter, and ADME/T analysis. RESULTS: Open arm duration and entries were comparable between 200 mg/kg b.w. group (184.45 ± 1.00 s and 6.25 ± 1.11, respectively) and that of diazepam treated group (180.02 s ± 0.40 and 6.10 ± 0.05, respectively). Time spent in the light cubicle was higher (46.86 ± 0.03%), similar to that of diazepam (44.33 ± 0.64%), suggesting its potent anxiolytic activity. A delayed onset of immobility and lowered immobility time was seen at both the treatment doses (FST: 93.7 ± 1.70 and 89.1 ± 0.40 s; TST: 35.05 ± 2.75 and 38.50 ± 4.10 s) and the standard drug imipramine (FST: 72.7 ± 3.72 and TST: 30.01 ± 2.99 s), indicative of its antidepressant ability. In silico studies predicted doripenem to induce anxiolytic and antidepressant activity by inhibiting human potassium channel KCSA-FAB and human serotonin transporter proteins, respectively. CONCLUSIONS: EEMC is a rich source of bioactive compounds with strong antidepressant and anxiolytic properties.