Antidiabetic Inhibitors Research Articles

In vitro α-glucosidase, docking and density functional theory studies on novel azide metal complexes.

Aim: The goal of this study is to synthesize new metal complexes containing N-methyl-1-(pyridin-2-yl)methanimine and azide ligands as α-glucosidase inhibitors for Type 2 diabetes. Materials & methods: The target complexes (12-16) were synthesized by reacting N-methyl-1-(pyridin-2-yl)methanimine (L1) with sodium azide in the presence of corresponding metal salts. The investigation of target protein interactions, vibrational, electronic and nonlinear optical properties for these complexes was performed by molecular docking and density functional theorystudies. Results: Among these complexes, complex 13 (IC50=0.2802±0.62μM) containing Hg ion showed the highest α-glucosidase inhibitory property. On the other hand, significant results were detected for complexes containing Cu and Ag ions. Conclusion: Complex 13 may be an alternate anti-diabetic inhibitor according to in vitro/docking results.

Exploring Type II Diabetes Inhibitors from Genus Daphne Plant-species: An Integrated Computational Study.

Plant species of the genus Daphne clasps a historical background with a potential source of bioactive phytochemicals such as flavonoids and daphnodorins. These compounds manifest a significant chemotaxonomic value in drug discovery. Their flair comprehensive pharmacological, phytochemical, biological, catalytic, and clinical utilities make them exclusively unique. This study was conducted to investigate the optimization and structure-based virtual screening of these peculiar analogs. The majority of the active constituents of medicines are obtained from natural products. Previously, before the invention of virtual screening methods or techniques, almost 80% of drugs were obtained from natural resources. Comparing reported data to drug discovery from 1981 to 2007 signifies that half of the FDA-approved drugs are obtained from natural resources. It has been reported that structures of natural products that have particularities of structural diversity, biochemical specification, and molecular properties make them suitable products for drug discovery. These products basically have unique chiral centers which increase their structural complexity than the synthesized drugs. This work aimed to probe the use of daphnodorins analogs for the first time as antidiabetic inhibitors based on significant features and to determine the potential of daphnodorin analogs as antidiabetic inhibitors through computational analysis and structure-based virtual screening. A dataset of 38 compounds was selected from different databases, including PubChem and ZINC, for computational analysis, and optimized compounds were docked against various co-crystallized structures of inhibitors, antagonists, and receptors which were downloaded from PDB by using AutoDock Vina (by employing Broyden-Fletcher-Goldfarb-Shanno method), Discovery studio visualizer 2020, PYMOL (Schrodinger). Docking results were further validated by Molecular dynamic simulation and MM-GBSA calculation. Quantitative structure-activity relationship (QSAR) was reported by using Gaussian 09W by intimating Density Functional Theory (DFT). Using this combination of multi-approach computational strategy, 14 compounds were selected as potential exclusive lead compounds, which were analyzed through ADMET studies to pin down their druglike properties and toxicity. At significant phases of drug design approaches regular use of molecular docking has helped to promote the separation of important representatives from 38 pharmaceutically active compounds by setting a threshold docking score of -9.0 kcal/mol which was used for their exposition. Subsequently, by employing a threshold it was recognized that 14 compounds proclaimed this threshold for antidiabetic activity. Further, molecular dynamic simulation, MM-GBSA, ADMET, and DFT results screened out daphnegiralin B4 (36) as a potential lead compound for developing antidiabetic agents. Our analysis took us to the conclusion that daphnegiralin B4 (36) among all ligands comes out to be a lead compound having drug-like properties among 38 ligands being non-carcinogenic and non-cytotoxic which would benefit the medical community by providing significant drugs against diabetes. Pragmatic laboratory investigations identified a new precursor to open new doors for new drug discovery.

Synthesis of zinc phthalocyanine complex containing tetra propanoic acid groups: Electronic properties and inhibitory effects on some metabolic enzymes

In the new study, first the synthesis and characterization of 2, 10, 16, 24-Tetrakis-3-(phenoxy) propanoic acid phthalocyaninato zinc (II)(4) and its starting compound are presented. The aggregation properties of compound (4) were investigated with the UV–visible spectrum, and the excitation and emission properties were investigated with the fluorescence spectra. The new compounds were characterized by IR, UV-visible, Mass and 1H NMR spectroscopy. These 3-(3,4-dicyanophenoxy) propanoic acid (3) and compound (4) had effective inhibition against α-glycosidase, α-amylase, butyrylcholinesterase and acetylcholinesterase. IC50 values were found as 4.21–6.57 µM for AChE, 0.32–1.88 µM for BChE, 47.14–62.07 µM for α-amylase, and 13.41–21.82 µM for α-glycosidase. By molecular docking study, compared to reference compounds (tacrine and acarbose) of compound (4) [-9.25 kcal/mol for AChE; -9.30 kcal/mol for BChE; -6.50 kcal/mol for α-amylase and -8.49 kcal/mol for α-glycosidase seem to be more effective and promising. Drug development for the treatment of diabetes, hyperglycemia, and obesity has as one of its design goals the creation of molecules that are α-amylase and α-glycosidase inhibitors. As a result, compound (4) can have promising anti Alzheimer drug potential and record as novel anti-diabetic inhibitors.

Synthesis, biological evaluation and molecular docking study of indazole based schiff base analogues as new anti-diabetic inhibitors

Indazole-based Schiff base analogues (1–27) were synthesized by a three-step reaction pathway starting from 1-methyl-1H-indazole-3-carboxylic acid as the basic compound. The structure of the new indazoles was characterized and confirmed by mass spectral analyses as well as NMR spectroscopic data. All synthesized analogues were screened for their in vitro α-glucosidase and α-amylase inhibitory activities. All analogues of the series exhibited good inhibitory potentials, with IC50 values ranging from 0.40 ± 0.01 to 16.20 ± 0.30 µM for α-glucosidase and 0.70 ± 0.01 to 17.40 ± 0.30 µM for α-amylase as compared to the standard drug acarbose (IC50 = 12.90 ± 0.10 and 12.80 ± 0.10 µM, respectively). The most effective analogue of the series is analogue 22 having 3‑hydroxyl groups with an IC50 value of 0.40 ± 0.01 µM and 0.70 ± 0.01 µM for α-glucosidase and α-amylase, respectively. Structure-activity relationship was carried out, which mainly depends upon the nature, number, position, and electron donating/withdrawing effect of the substituent(s) attached to the phenyl ring. To investigate the binding interaction of the potent analogue with the active site of an enzyme, molecular docking studies were carried out.

Identification of antidiabetic inhibitors from Allophylus villosus and Mycetia sinensis by targeting α-glucosidase and PPAR-γ: In-vitro, in-vivo, and computational evidence

Diabetes mellitus (DM) is a metabolic disorder arising from insulin deficiency and defectiveness of the insulin receptor functioning on transcription factor where the body loses control to regulate glucose metabolism in β-cells, pancreatic and liver tissues to homeostat glucose level. Mainstream medicines used for DM are incapable of restoring normal glucose homeostasis and have side effects where medicinal plant-derived medicine administrations have been claimed to cure diabetes or at least alleviate the significant symptoms and progression of the disease by the traditional practitioners. This study focused on screening phytocompounds and their pharmacological effects on anti-hyperglycemia on Swiss Albino mice of n-hexane, ethyl acetate, and ethanol extract of both plants Mycetia sinensis and Allophylus villosus as well as the in-silico investigations. Qualitative screening of phytochemicals and total phenolic and flavonoid content estimation were performed significantly in vitro analysis. FTIR and GC–MS analysis précised the functional groups and phytochemical investigations where FTIR scanned 14, 23 & 17 peaks in n-hexane, ethyl acetate, and ethanol extracts of Mycetia sinensis whereas the n-hexane, ethyl acetate, and ethanol extracts of Allophylus villosus scanned 11 peaks, 18 peaks, and 29 peaks, respectively. In GC–MS, 24 chemicals were identified in Mycetia sinensis extracts, whereas 19 were identified in Allophylus villosus extracts. Moreover, both plants' ethyl acetate and ethanol fractioned extracts were reported significantly (p < 0.05) with concentrations of 250 mg and 500 mg on mice for oral glucose tolerance test, serum creatinine test and serum alkaline phosphatase test. In In silico study, a molecular docking study was done on these 43 phytocompounds identified from Mycetia sinensis and Allophylus villosus to identify their binding affinity to the target Alpha Glucosidase (AG) and Peroxisome proliferator-activated receptor gamma protein (PPARG). Therefore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, quantum mechanics-based DFT (density-functional theory), and molecular dynamics simulation were done to assess the effectiveness of the selected phytocompounds. According to the results, phytocompounds such as 2,4-Dit-butyl phenyl 5-hydroxypentanoate and Diazo acetic acid (1S,2S,5R)-2-isopropyl-5-methylcyclohexyl obtained from Mycetia sinensis and Allophylus villosus extract possess excellent antidiabetic activities.

In Vitro and in silico studies to explore potent antidiabetic inhibitor against human pancreatic alpha-amylase from the methanolic extract of the green microalga Chlorella vulgaris

Today’s era and lifestyle have led to a quick rise in cases of diabetes. Diabetes mellitus (DM) has risen to the top of the list of serious diseases and stems from different health disorders. Human pancreatic alpha-amylase (HPA) enzyme plays a critical role in the digestion of carbohydrates, and inhibitors of alpha-amylase have been investigated as a way to slow the absorption of carbohydrates and reduce postprandial (after meal) hyperglycemia in patients with diabetes. Recently algal derivatives have been studied for their potential as a new drug against diabetes and other diseases. The study is aimed to find active biochemical compounds from the methanolic extract of Chlorella vulgaris. The in vitro studies were carried out and the results revealed that methanolic extract from C. vulgaris showed abundant inhibition efficacy of the α-amylase (IC50 of about 2.66 µg/mL) compared to acarbose (IC50 of about 2.85 µg/mL), a standard, commercial inhibitor. All the bioactive compounds from the methanolic extract were identified from the GCMS study and considered for in silico evaluation. Out of 14 bioactive compounds from GCMS, compound C3 showed higher docking energy (-8.3 kcal/mol) compared to other compounds. Subsequently, the comparative molecular dynamic simulation of apo and ligand-bound (compound C3 and acarbose) α-amylase complexes showed overall structural stability for compound C3 at the active site of α-amylase from various MD analyses. Hence, we believe, the bioactive compounds identified from GCMS may assist in diabetic therapeutics. Moreover, the compound C3 identified in this study could be a potential antidiabetic therapeutic inhibitor. Communicated by Ramaswamy H. Sarma

In Silico Screening and Identification of Antidiabetic Inhibitors Sourced from Phytochemicals of Philippine Plants against Four Protein Targets of Diabetes (PTP1B, DPP-4, SGLT-2, and FBPase).

Current oral medications for type 2 diabetes target a single main physiological mechanism. They either activate or inhibit receptors to enhance insulin sensitivity, increase insulin secretion, inhibit glucose absorption, or inhibit glucose production. In advanced stages, combination therapy may be required because of the limited efficacy of single-target drugs; however, medications are becoming more costly, and there is also the risk of developing the combined side effects of each drug. Thus, identifying a multi-target drug may be the best strategy to improve treatment efficacy. This study sees the potential of 2657 Filipino phytochemicals as a source of natural inhibitors against four targets of diabetes: PTP1B, DPP-4, SGLT-2, and FBPase. Different computer-aided drug discovery techniques, including ADMET profiling, DFT optimization, molecular docking, MD simulations, and MM/PBSA energy calculations, were employed to elucidate the stability and determine the binding affinity of the candidate ligands. Through in silico methods, we have identified seven potential natural inhibitors against PTP1B, DPP-4, and FBPase, and ten against SGLT-2. Eight plants containing at least one natural inhibitor of each protein target were also identified. It is recommended to further investigate the plants' potential to be transformed into a safe and scientifically validated multi-target drug for diabetes therapies.

Euonymus laxiflorus Champ. Bioactive Compounds Inhibited α-Glucosidase and Protein Phosphatase 1B – A Computational Approach Towards the Discovery of Antidiabetic Drugs

Euonymus laxiflorus Champ. has recently proven for its antidiabetic potential yet its ingredientactivity relationship is vastly unknown. A combination of quantum calculation, molecular docking simulation, physicochemical analysis, and ADMET was utilised together for the theoretical argument on potentiality of bioactively undetermined components (1-15) against α-glucosidase (PDB-3W37) and tyrosine phosphatase 1B (UniProtKB-PTP1B). Dipole moment values indicate the favoured bio-medium compatibility of 10 (6.370 Debye), 12 (6.381 Debye), and 15 (8.446 Debye), while the values discourage the potential of 5 (0.792 Debye) and 11 (0.905 Debye). Molecular electrostatic potential maps imply the intermolecular interacting flexibility of 6-10 and 12-15. Docking-based simulation predicts the most effective inhibitory systems, i.e. (i) ligand- 3W37: 10 ≈ 11 (DS -11.7 kcal.mol-1) ≈ 3 (DS -11.6 kcal.mol-1) &gt; 7 ≈ 12 (DS -11.1 kcal.mol-1); (ii) ligand-PTP1B: 11 (DS -12.0 kcal.mol-1) &gt; 13 (DS -11.8 kcal.mol-1) &gt; 5 (DS -11.2 kcal.mol-1) &gt; 3 (DS -11.0 kcal.mol-1). Polarisability justifies the bio-medium compatibility of 10 (70.8 Å3) and 15 (64.7 Å3) while especially opposes the potentiality of 11 (19.1 Å3). Physicochemical and pharmacological properties support the suitability for further drug-like development. Altogether, 10 (7-Hydroxy-6,7-dihydro-cis/trans-geraniate, 3-O-α-L-arabinopyranosyl (1→6)-β-Dglucupyranosyl) and 15 (3,5-dimethoxy-4-hydroxyphenol)-1-O-β-D-(6'-O-galloyl)- glucopyranoside) are allocated as the most promising antidiabetic inhibitors.

In-silico Screening and Identification of Antidiabetic Inhibitors Sourced from Phytochemicals of Philippine Plants against Four Protein Targets of Diabetes (PTP1B, DPP-4, SGLT-2, and FBPase)

In-silico Screening and Identification of Antidiabetic Inhibitors Sourced from Phytochemicals of Philippine Plants against Four Protein Targets of Diabetes (PTP1B, DPP-4, SGLT-2, and FBPase)

The importance of including the C-terminal domain of PTP1B1-400 to identify potential antidiabetic inhibitors

In the present work, we studied the inhibitory and kinetic implications of classical PTP1B inhibitors (chlorogenic acid, ursolic acid, suramin) using three enzyme constructs (hPTP1B1-285, hPTP1B1-321, and hPTP1B1-400). The results indicate that the unstructured region of PTP1B (300-400 amino acids) is very important both to obtain optimal inhibitory results and propose classical inhibition mechanisms (competitive or non-competitive) through kinetic studies. The IC50 calculated for ursolic acid and suramin using hPTP1B1-400 are around four and three times lower to the short form of the enzyme, the complete form of PTP1B, the one found in the cytosol (in vivo). On the other hand, we highlight the studies of enzymatic kinetics using the hPTP1B1-400 to know the type of enzymatic inhibition and to be able to direct docking studies, where the unstructured region of the enzyme can be one more option for binding compounds with inhibitory activity.

Pumpkin Rind and Seeds Extracts Inhibit α - Glucosidase and Nitric Oxide Production and Promote Chlorella ellipsoidea Growth in Culture

The objective of this work was to investigate the potential of pumpkin rind and seed on antidiabetic and anti-inflammatory activities and the underlying mechanism. Therefore, this work was carried out to determine the antidiabetic activity using inhibitory activities of pumpkin rind and seeds extracts on α - glucosidase and the anti-inflammatory activity via inhibitory activity on nitric oxide production. And also, the potential of the pumpkin rind and seeds on culture of Chlorella ellipsoidea was determined. Determination of inhibitory activity on α - glucosidase was performed using α - glucosidase assay, while the Griess assay was employed for the inhibition on Nitric oxide (NO) -production. The pumpkin seed extract inhibited α - glucosidase more potent than the pumpkin rind extract (IC50 of 321.36 vs. 326.18 µg/mL). However, the activities of the extracts were less potent than that of Acarbose (IC50 of 317.26 µg/mL). Application of the extracts at the highest concentration, 500 µg/mL, the pumpkin seed extract displayed the inhibition of NO production higher than the pumpkin rind extract did (18.01 ± 1.57 % vs. 14.99 ± 1.94 %). Study on the effects of pumpkin rind and seeds on C. ellipsoidea culture revealed that the optimum media was the 7th medium (NPK+ mixture of pumpkin seed water and Blue-Green Medium (BG-11), 1:4) which generated the growth of C. ellipsoidea for 28 days with the Optical Density (OD) value of 1.43 ± 0.01 followed by BG-11 medium OD value of 1.41 ± 0.02) and the 3rd medium (NPK+ mixture of pumpkin rind water and BG-11, 1:1, OD value of 1.32 ± 0.01), respectively. The chemical contents of C. ellipsoidea cultured in 7th medium contained 54.25 ± 0.06 % protein, 15.95 ± 0.87 % carbohydrates, 9.35 ± 0.05 % fat, and 20.30 ± 0.33 % ash, meanwhile 53.37 ± 0.77 % protein, 12.83 ± 0.62 % carbohydrates, 17.80 ± 0.23 % fat, and 23.30 ± 1.33 % ash in the 3rd medium. The results obtained from this investigation indicate that pumpkin rind and seeds not only can be exploited for the antidiabetic and anti-inflammatory components but also can be applied instead of the conventional medium for the culture of C. ellipdoidea. Therefore, bio-waste from pumpkin could be potentially utilized as the source of natural antidiabetic inhibitors, anti-inflammatory drugs and the effective components of C. ellipdoidea culture media. HIGHLIGHTS The pumpkin rind and seed extracts possess antidiabetic and anti-inflammatory properties The extracts from pumpkin rind and seeds exhibit antidiabetic activity via α- glucosidase inhibition The extracts from pumpkin rind and seeds display anti-inflammatory activity by inhibiting on nitric oxide (NO) production The extracts from pumpkin rind and seeds could be potentially utilized as a source of natural antidiabetic inhibitors and anti-inflammatory drugs The bio-waste, pumpkin rind and seeds, could be used as the effective components of ellipdoidea culture medium GRAPHICAL ABSTRACT

Newly synthesised oxime and lactone derivatives from Dipterocarpus alatus dipterocarpol as anti-diabetic inhibitors: experimental bioassay-based evidence and theoretical computation-based prediction.

Dipterocarpus alatus-derived products are expected to exhibit anti-diabetes properties. Natural dipterocarpol (1) was isolated from Dipterocarpus alatus collected in Quang Nam province, Vietnam; afterwards, 20 derivatives including 13 oxime esters (2 and 3a–3m) and 7 lactones (4, 5, 6a–6e) were semi-synthesised. Their inhibitory effects towards diabetes-related proteins were investigated experimentally (α-glucosidase) and computationally (3W37, 3AJ7, and PTP1B). Except for compound 2, the other 19 compounds (3a–3m, 4, 5, and 6a–6d) are reported for the first time, which were modified at positions C-3, C-24 and C-25 of the dipterocarpol via imidation, esterification, oxidative cleavage and lactonisation reactions. A framework based on docking-QSARIS combination was proposed to predict the inhibitory behaviour of the ligand-protein complexes. Enzyme assays revealed the most effective α-glucosidase inhibitors, which follow the order 5 (IC50 of 2.73 ± 0.05 μM) > 6c (IC50 of 4.62 ± 0.12 μM) > 6e (IC50 of 7.31 ± 0.11 μM), and the computation-based analysis confirmed this, i.e., 5 (mass: 416.2 amu; polarisability: 52.4 Å3; DS: −14.9 kcal mol−1) > 6c (mass: 490.1 amu; polarisability: 48.8 Å3; DS: −13.7 kcal mol−1) > 6e (mass: 549.2 amu; polarisability: 51.6 Å3; DS: −15.2 kcal mol−1). Further theoretical justifications predicted 5 and 6c as versatile anti-diabetic inhibitors. The experimental results encourage next stages for the development of anti-diabetic drugs and the computational strategy invites more relevant work for validation.

Novel enantiopure isoxazolidine and C-alkyl imine oxide derivatives as potential hypoglycemic agents: Design, synthesis, dual inhibitors of α-amylase and α-glucosidase, ADMET and molecular docking study

In an effort to explore a new class of antidiabetic inhibitors, a new series of isoxazolidine and C-alkyl imine oxide derivatives scaffolds were designed, synthesized and fully characterized. The newly synthesized analogues were evaluated for their human pancreatic α-amylase (HPA) and human lysosomal acid-α-glucosidase (HLAG) inhibitory activities and have shown a higher potency than acarbose. The compounds 7b (23.1 ± 1.1 μM) and 7a (36.3 ± 1.6 μM) were identified as the potent HPA and HLAG inhibitors with inhibitory effect up to 9 and 21-fold higher than acarbose, respectively. Antihyperglycemic activity results were supported by molecular docking approach of the most potent compounds 7b and 7a showing stronger interactions with the active site of HPA and HLAG as well as by in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) profile suggesting their satisfactory oral druglikeness without toxic effect. Therefore, it can be concluded that both 7b and 7a can be used as effective lead molecules for the development of HPA and HLAG inhibitors for the management of T2DM.

Identification of Antidiabetic Metabolites from Paederia foetida L. Twigs by Gas Chromatography-Mass Spectrometry-Based Metabolomics and Molecular Docking Study.

Paederia foetida L. (Rubiaceae) is a climber which is widely distributed in Asian countries including Malaysia. The plant is traditionally used to treat various diseases including diabetes. This study is to evaluate the enzymatic inhibition activity of Paederia foetida twigs extracts and to identify the metabolites responsible for the bioactivity by gas chromatography-mass spectrometry (GC-MS) metabolomics profiling. Three different twig extracts, namely, hexane (PFH), chloroform (PFC), and methanol (PFM), were submerged for their α-amylase and α-glucosidase inhibition potential in 5 replicates for each. Results obtained from the loading column scatter plot of orthogonal partial least square (OPLS) model revealed the presence of 12 bioactive compounds, namely, dl-α-tocopherol, n-hexadecanoic acid, 2-hexyl-1-decanol, stigmastanol, 2-nonadecanone, cholest-8(14)-en-3-ol, 4,4-dimethyl-, (3β,5α)-, stigmast-4-en-3-one, stigmasterol, 1-ethyl-1-tetradecyloxy-1-silacyclohexane, ɣ-sitosterol, stigmast-7-en-3-ol, (3β,5α,24S)-, and α-monostearin. In silico molecular docking was carried out using the crystal structure α-amylase (PDB ID: 4W93) and α-glucosidase (PDB ID: 3WY1). α-Amylase-n-hexadecanoic acid exhibited the lowest binding energy of -2.28 kcal/mol with two hydrogen bonds residue, namely, LYS178 and TYR174, along with hydrophobic interactions involving PRO140, TRP134, SER132, ASP135, and LYS172. The binding interactions of α-glucosidase-n-hexadecanoic acid complex ligand also showed the lowest binding energy among 5 major compounds with the energy value of -4.04 kcal/mol. The complex consists of one hydrogen bond interacting residue, ARG437, and hydrophobic interactions with ALA444, ASP141, GLN438, GLU432, GLY374, LEU373, LEU433, LYS352, PRO347, THR445, HIS348, and PRO351. The study provides informative data on the potential antidiabetic inhibitors identified in Paederia foetida twigs, indicating the plant has the therapeutic effect properties to manage diabetes.

Purification and identification of a novel antidiabetic peptide from Chinese giant salamander (Andrias davidianus) protein hydrolysate against α-amylase and α-glucosidase

ABSTRACTThis study aimed to purify and identify a novel antidiabetic peptides from Chinese giant salamander (Andrias davidianus) protein hydrolysate and to evaluate its anti-diabetic properties against α-amylase and α-glucosidase. The isolation was done by gel filtration, reverse phase chromatography (RF-HLPC), and finally peptide and amino acid sequences were identified by LC/MS/MS system. Our results revealed five novel peptides that strongly inhibited α-amylase and α-glucosidase. The peptides’ amino acid sequences were Cys-Ser-Ser-Val (MW = 393.99 Da), Tyr-Ser-Phe-Arg (MW = 570.99 Da), Ser-Ala-Ala-Pro (MW = 343.89 Da), Pro-Gly-Gly-Pro (MW = 325.99 Da) and Leu-Gly-Gly-Gly-Asn (MW = 415.99 Da) possessing α-amylase inhibitory activity IC50 of 13.76 × 103, 10.82 × 103, 4.46 × 103, 4.23 × 103, and 2.86 × 103 µg/mL, respectively; and for α-glucosidase with IC50 of 206.00, 162.00, 66.90, 63.50, and 42.93 µg/mL, respectively. Intriguingly, the peptide LGGGN showed higher inhibition on both α-amylase and α-glucosidase and could be considered as a potential anti-diabetic inhibitor.

Anti-diabetic activity peptides from albumin against α-glucosidase and α-amylase

The objectives of this study were to identify novel peptides from albumin, and to evaluate and validate the anti-diabetic activity of peptides against α-glucosidase and α-amylase. In the research, albumin hydrolysate was purified and identified, tandem MS was adapted to characterise the amino acid sequences of peptides from the hydrolysate. In addition, anti-diabetic effects of the peptides with α-glucosidase and α-amylase inhibitory activity have been performed. The present work found eight novel peptides from albumin. Results also suggested that peptide KLPGF had α-glucosidase inhibitory activity with an IC50 of 59.5±5.7μmoll−1 and α-amylase inhibitory activity with an IC50 of 120.0±4.0μmoll−1. In conclusion, the results revealed that the peptide KLPGF was a potential anti-diabetic inhibitor.

Discovery of DPP IV Inhibitors by Pharmacophore Modeling and QSAR Analysis followed by in silico Screening

Dipeptidyl peptidase IV (DPP IV) deactivates the natural hypoglycemic incretin hormones. Inhibition of this enzyme should restore glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, the pharmacophoric space of DPP IV was explored using a set of 358 known inhibitors. Thereafter, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors that yield selfconsistent and predictive quantitative structure-activity relationships (QSAR) (r(2) (287)=0.74, F-statistic=44.5, r(2) (BS)=0.74, r(2) (LOO)=0.69, r(2) (PRESS) against 71 external testing inhibitors=0.51). Two orthogonal pharmacophores (of cross-correlation r(2)=0.23) emerged in the QSAR equation suggesting the existence of at least two distinct binding modes accessible to ligands within the DPP IV binding pocket. Docking experiments supported the binding modes suggested by QSAR/pharmacophore analyses. The validity of the QSAR equation and the associated pharmacophore models were established by the identification of new low-micromolar anti-DPP IV leads retrieved by in silico screening. One of our interesting potent anti-DPP IV hits is the fluoroquinolone gemifloxacin (IC(50)=1.12 muM). The fact that gemifloxacin was recently reported to potently inhibit the prodiabetic target glycogen synthase kinase 3beta (GSK-3beta) suggests that gemifloxacin is an excellent lead for the development of novel dual antidiabetic inhibitors against DPP IV and GSK-3beta.