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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.

The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 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 Aβ. 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.

IntroductionLectins 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.MethodsThe 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 DiscussionOf 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, β-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.ConclusionHowever, 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.

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.

The anti-diabetic potential of whole unripe jackfruit (peel with pulp, flake, and seed) was investigated using inhibitory assays for α-glucosidase, α-amylase, aldose reductase, and glycation at multiple stages. Using activity-guided repeated fractionation on a silica gel column chromatography, dietary flavonoid rutin with potent antihyperglycemic activity was extracted from the methanol extract of whole jackfruit flour (MJ). Rutin was found to inhibit both α-glucosidase (IC50: 7.86 µg/mL) and α-amylase (IC50: 22.00 µg/mL) in a competitive manner of inhibition with low Ki values. In addition, in vitro glycation experiments revealed that rutin prevented each stage of protein glycation as well as the production of intermediate molecules. Furthermore, rutin significantly inhibited aldose reductase (IC50: 2.75 µg/mL) in a non-competitive manner. During in silico studies, molecular docking and molecular dynamics simulation studies have suggested that rutin has a high binding affinity for the enzymes studied, which could explain its inhibitory effects. Rutin interacted with the key residues of the target enzymes’ inhibitor binding sites. Compared to the controls used, rutin had a higher binding efficiency as well as stability in the inhibitor binding pocket of the target enzymes. According to our findings, the presence of rutin is more likely to be associated with the potential of MJ in antihyperglycemic activity via inhibition of α-glucosidase and in anti-diabetic action via inhibition of the polyol pathway and protein glycation. The bio-computational study indicates rutin as a potential lead inhibitor of all the target enzymes used and could be used as an effective anti-diabetic drug in the near future.

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.

Diabetes mellitus is a major global health concern in the current scenario which is chiefly characterized by the rise in blood sugar levels or hyperglycemia. In the context, DPP4 enzyme plays a critical role in glucose homeostasis. DPP4 targets and inactivates incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) as physiological substrates, which are essential to regulate the amount of insulin that is secreted after eating. Since the inactivation of incretins occurs, the hyperglycemic conditions continue to rise, and result in adverse physiological conditions linked with diabetes mellitus. Hence, inhibition of DPP4 has been the center of focus in the present antidiabetic studies. Although few DPP4 inhibitor drugs, such as alogliptin, saxagliptin, linagliptin, and sitagliptin, are available, their adverse effects on human metabolism are undeniable. Therefore, it becomes essential for the phytochemical intervention of the disease using computational methods prior to performing in vitro and in vivo studies. In this regard, we used an in-silico approach involving molecular docking, molecular dynamics simulations, and binding free energy calculations to investigate the inhibitory potential of Ocimum tenuiflorum phytocompounds against DPP4. In this regard, three phytocompounds (1S-α-pinene, β-pinene, and dehydro-p-cymene) from O. tenuiflorum have been discovered as the potential inhibitors of the DPP4 protein. To summarize, from our in-silico experiment outcomes, we propose dehydro-p-cymene as the potential lead inhibitor of DPP4 protein, thereby discovering new a phytocompound for the effective management of hyperglycemia and diabetes mellitus. The reported compound can be taken for in vitro and in vivo analyses in near future.

Thymus vulgaris Linn. is a medicinal and culinary herb from the Southern European region known for its anti-infective, cardioprotective, gastroprotective, anti-inflammatory, and immunomodulatory activities since the Egyptian era. The reported pharmacological activities of T. vulgaris L. include antibacterial, antioxidant, anti-inflammatory, antiviral, and anti-cancerous activities. In this review, a comprehensive approach is put forth to scrutinize and report the available data on phytochemistry, ethnopharmacology, pharmacology, and toxicology of the plant. The different extracts and essential oil obtained from the plant have been assessed and reported to treat ailments like microbial infections, inflammation, non-communicable diseases like cancer, and sexually transmitted diseases like HIV-1 and Herpes. The literature review has also indicated the use of volatile oils, phenolic acids, terpenoids, flavonoids, saponins, steroids, tannins, alkaloids, and polysaccharides in pharmacotherapy. Applications of these compounds including antidiabetic, anti-Alzheimer's, cardio, neuro and hepatoprotective, anti-osteoporosis, sedative, immunomodulatory, antioxidant, anti-tyrosinase, antispasmodic, antinociceptive, gastroprotective, anticonvulsant, antihypertensive, antidepressant, anti-amnesia, and anti-helminthic activities have been mentioned. Further, based on research gaps, recommendations have been provided to evaluate T. vulgaris L. systematically to develop plant-based drugs, nutraceuticals, and to evaluate their clinical efficiency and safety.

The crystal compound was synthesized and characterized using conventional analytical techniques. The compound C19H21O3 crystallizes in a monoclinic crystal system with the space group P21/c. The crystal structure is stabilized by C-H…O interactions. The structure is further reinforced by π-π interactions. During in vitro inhibition of α-glucosidase, the crystal compound exhibited a significant inhibition of the enzyme (IC50: 10.30 ± 0.25 µg/mL) in comparison with the control, acarbose (IC50: 12.00 ± 0.10 µg/mL). Molecular docking studies were carried out for the crystal compound with the α-glucosidase protein model, which demonstrated that the crystal molecule has a good binding affinity (−10.8 kcal/mol) compared with that of acarbose (−8.2 kcal/mol). The molecular dynamics simulations and binding free energy calculations depicted the stability of the crystal molecule throughout the simulation period (100 ns). Further, a Hirshfeld analysis was carried out in order to understand the packing pattern and intermolecular interactions. The energy difference between the frontier molecular orbitals (FMO) was 4.95 eV.

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.

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.

For the first time, α-glucosidase, α-amylase, aldose reductase, and glycation at multiple stages inhibitory assays were used to explore the antidiabetic potential of whole unripe jackfruit (peel with pulp, flake, and seed). Two polyphenols (phenolic acids) with strong antihyperglycaemic activity were isolated from the methanol extract of whole jackfruit flour (MJ) using activity-guided repeated fractionation on a silica gel column chromatography. The bioactive compounds isolated were identified as 3-(3,4-Dihydroxyphenyl)-2-propenoic acid (caffeic acid: CA) and 4-Hydroxy-3,5-dimethoxybenzoic acid (syringic acid: SA) after various physicochemical and spectroscopic investigations. CA (IC50: 8.0 and 26.90 µg/mL) and SA (IC50: 7.5 and 25.25 µg/mL) were identified to inhibit α-glucosidase and α-amylase in a competitive manner with low Ki values. In vitro glycation experiments further revealed that MJ and its components inhibited each stage of protein glycation as well as the generation of intermediate chemicals. Furthermore, CA (IC50: 3.10) and SA (IC50: 3.0 µg/mL) inhibited aldose reductase effectively in a non-competitive manner, respectively. The binding affinity of these substances towards the enzymes examined has been proposed by molecular docking and molecular dynamics simulation studies, which may explain their inhibitory activities. The found potential of MJ in antihyperglycaemic activity via inhibition of α-glucosidase and in antidiabetic action via inhibition of the polyol pathway and protein glycation is more likely to be related to the presence of the phenolic compounds, according to our findings.

Summary: 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 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.