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.

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.

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.

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.

Benzodioxole grafted spirooxindole pyrrolidinyl derivatives: synthesis, characterization, molecular docking and anti-diabetic activity.

A highly stereoselective, three-component method has been developed to synthesize pyrrolidine and pyrrolizidine containing spirooxindole derivatives. The interaction between the dipolarophile α,ß-unsaturated carbonyl compounds and the dipole azomethine ylide formed in situ by the reaction of 1,2-dicarbonyl compounds and secondary amino acids is referred to as the 1,3-dipolar cycloaddition reaction. The reaction conditions were optimized to achieve excellent stereo- and regioselectivity. Shorter reaction time, simple work-up and excellent yields are the salient features of the present approach. Various spectroscopic methods and single crystal X-ray diffraction examinations of one example of compound 6i validated the stereochemistry of the expected products. The anti-diabetic activity of the newly synthesized spirooxindole derivatives was tested against the α-glucosidase and α-amylase enzymes. Compound 6i was found to exhibit potent inhibition activity against α-glucosidase and α-amylase enzymes which is further evidenced by molecular docking studies.

Discovery of Novel Coumarin Derivatives as Potential Dual Inhibitors against α-Glucosidase and α-Amylase for the Management of Post-Prandial Hyperglycemia via Molecular Modelling Approaches.

Coumarin derivatives are proven for their therapeutic uses in several human diseases and disorders such as inflammation, neurodegenerative disorders, cancer, fertility, and microbial infections. Coumarin derivatives and coumarin-based scaffolds gained renewed attention for treating diabetes mellitus. The current decade witnessed the inhibiting potential of coumarin derivatives and coumarin-based scaffolds against α-glucosidase and α-amylase for the management of postprandial hyperglycemia. Hyperglycemia is a condition where an excessive amount of glucose circulates in the bloodstream. It occurs when the body lacks enough insulin or is unable to correctly utilize it. With open-source and free in silico tools, we have investigated novel 80 coumarin derivatives for their inhibitory potential against α-glucosidase and α-amylase and identified a coumarin derivative, CD-59, as a potential dual inhibitor. The ligand-based 3D pharmacophore detection and search is utilized to discover diverse coumarin-like compounds and new chemical scaffolds for the dual inhibition of α-glucosidase and α-amylase. In this regard, four novel coumarin-like compounds from the ZINC database have been discovered as the potential dual inhibitors of α-glucosidase and α-amylase (ZINC02789441 and ZINC40949448 with scaffold thiophenyl chromene carboxamide, ZINC13496808 with triazino indol thio phenylacetamide, and ZINC09781623 with chromenyl thiazole). To summarize, we propose that a coumarin derivative, CD-59, and ZINC02789441 from the ZINC database will serve as potential lead molecules with dual inhibition activity against α-glucosidase and α-amylase, thereby discovering new drugs for the effective management of postprandial hyperglycemia. From the reported scaffold, the synthesis of several novel compounds can also be performed, which can be used for drug discovery.

Defining the Role of Isoeugenol from Ocimum tenuiflorum against Diabetes Mellitus-Linked Alzheimer's Disease through Network Pharmacology and Computational Methods.

The present study involves the integrated network pharmacology and phytoinformatics-based investigation of phytocompounds from Ocimum tenuiflorum against diabetes mellitus-linked Alzheimer's disease. It aims to investigate the mechanism of the Ocimum tenuiflorum phytocompounds in the amelioration of diabetes mellitus-linked Alzheimer's disease through network pharmacology, druglikeness and pharmacokinetics, molecular docking simulations, GO analysis, molecular dynamics simulations, and binding free energy analyses. A total of 14 predicted genes of the 26 orally bioactive compounds were identified. Among these 14 genes, GAPDH and AKT1 were the most significant. The network analysis revealed the AGE-RAGE signaling pathway to be a prominent pathway linked to GAPDH with 50.53% probability. Upon the molecular docking simulation with GAPDH, isoeugenol was found to possess the most significant binding affinity (-6.0 kcal/mol). The molecular dynamics simulation and binding free energy calculation results also predicted that isoeugenol forms a stable protein-ligand complex with GAPDH, where the phytocompound is predicted to chiefly use van der Waal's binding energy (-159.277 kj/mol). On the basis of these results, it can be concluded that isoeugenol from Ocimum tenuiflorum could be taken for further in vitro and in vivo analysis, targeting GAPDH inhibition for the amelioration of diabetes mellitus-linked Alzheimer's disease.

Discovery of novel benzophenone integrated derivatives as anti-Alzheimer's agents targeting presenilin-1 and presenilin-2 inhibition: A computational approach.

The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aß42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precursor protein (APP) metabolism, affecting γ-secretase protease secretion, finally leading to the increased levels of Aß. In the absence of reported commercial pharmacotherapeutic agents targeting presenilins, we aim to propose benzophenone integrated derivatives (BIDs) as the potential inhibitors of presenilin proteins through in silico approach. The study evaluates the interaction of BIDs through molecular docking simulations, molecular dynamics simulations, and binding free energy calculations. This is the first ever computational approach to discover the potential inhibitors of presenilin proteins. It also comprises druglikeliness and pharmacotherapeutic potential analysis of the compounds. Out of all the screened BIDs, BID-16 was found to be the lead compound against both the presenilin proteins. Based on these results, one can evaluate BID-16 as an anti-Alzheimer's potential specifically targeting presenilin proteins in near future using in vitro and in vivo methods.

In silico identification of novel benzophenone-coumarin derivatives as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors.

In this study, we propose our novel benzophenone-coumarin derivatives (BCDs) as potent inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus, one of the key targets that are involved in the viral genome replication. We aim to evaluate the in silico antiviral potential of BCDs against this protein target, which involves molecular docking simulations, druglikeliness and pharmacokinetic evaluations, PASS analysis, molecular dynamics simulations, and computing binding free energy. Out of all the BCDs screened through these parameters, BCD-8 was found to be the most efficient and potent inhibitor of SARS-CoV-2 RdRp. During molecular docking simulation, BCD-8 showed an extensive molecular interaction in comparison with that of the standard control used, remdesivir. The druglikeliness and pharmacokinetic analyses also proved the efficiency of BCD-8 as an effective drug without adverse effects. Further, pharmacological potential analysis through PASS depicted the antiviral property of BCD-8. With these findings, we performed molecular dynamics simulations, where BCD-8 edged out remdesivir with its exemplary stable interaction with SARS-CoV-2 RdRp. Furthermore, binding free energy of both BCD-8 and remdesivir was calculated, where BCD-8 showed a lower binding energy and standard deviations in comparison with that of remdesivir. Moreover, being a non-nucleoside analogue, BCD-8 can be used effectively against SARS-CoV-2, whereas nucleoside analogues like remdesivir may become non-functional or less functional due to exonuclease activity of nsp14 of the virus. Therefore, we propose BCD-8 as a SARS-CoV-2 RdRp inhibitor, showing higher predicted efficiency than remdesivir in all the in silico experiments conducted.Communicated by Ramaswamy H. Sarma.

Evaluation of flavonoids from banana pseudostem and flower (quercetin and catechin) as potent inhibitors of α-glucosidase: An in silico perspective.

The amelioration of postprandial hyperglycemia in diabetic conditions could be accomplished by the inhibition of α-glucosidases, a set of intestinal carbohydrate digestive enzymes responsible for starch hydrolysis and its absorption. The ethnopharmacological profile of banana depicts the usage of different plant parts in conventional medicinal formulations. The antidiabetic studies of the plant have demonstrated their ability to inhibit α-glucosidase. Besides, our research group has reported the α-glucosidase inhibitory potential of the banana pseudostem and flower extracts in previous studies. In this study, we deliberate on the specific phytoconstituents of banana pseudostem and flower to evaluate their antidiabetic effects through an in silico perspective for the α-glucosidase inhibition. In this context, several phytoconstituents of banana pseudostem and flower identified through GC-MS analysis were retrieved from chemical databases. These phytochemicals were virtually screened through the molecular docking simulation process, from which only two flavonoids (catechin and quercetin) were selected based on their binding affinity and extent of interaction with the α-glucosidase target protein. The lower binding affinities of catechin and quercetin in comparison with that of acarbose as a control proved their binding efficiency with the target protein. In addition, acarbose showed subservient molecular interaction, forming an unfavourable acceptor-acceptor bond. The molecular dynamics simulations also depicted the effective binding and stability of the complexes formed with catechin and quercetin, in comparison with that of acarbose. Further, PASS analysis, druglikeliness, and pharmacokinetic assessments showed that both catechin and quercetin edge over acarbose in terms of drug-score and pharmacokinetic properties. With the positive results obtained from contemporary strategies, the two flavonoids from banana pseudostem and flower might be established as a considerable phototherapeutic approach to inhibit α-glucosidase. Communicated by Ramaswamy H. Sarma.