scholarly journals Exploring the Dual Inhibitory Activity of Novel Anthranilic Acid Derivatives towards α-Glucosidase and Glycogen Phosphorylase Antidiabetic Targets: Design, In Vitro Enzyme Assay, and Docking Studies

Molecules ◽  
2018 ◽  
Vol 23 (6) ◽  
pp. 1304
Author(s):  
Saleh Ihmaid
Keyword(s):  
Inhibitory Activity ◽  
Anthranilic Acid ◽  
Glycogen Phosphorylase ◽  
Enzyme Assay ◽  
Docking Studies ◽  
Anthranilic Acid Derivatives

scholarly journals An In Silico and an In Vitro Inhibition Analysis of Glycogen Phosphorylase by Flavonoids, Styrylchromones, and Pyrazoles

Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 306
Author(s):  
Sónia Rocha ◽  
Natália Aniceto ◽  
Rita C. Guedes ◽  
Hélio M. T. Albuquerque ◽  
Vera L. M. Silva ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
In Silico ◽  
Glycogen Phosphorylase ◽  
Inhibitory Effect ◽  
Docking Studies ◽  
Potent Inhibitory Effect ◽  
Key Enzyme ◽  
Experimental Findings

Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway. GP inhibitors are currently under investigation as a new liver-targeted approach to managing type 2 diabetes mellitus (DM). The aim of the present study was to evaluate the inhibitory activity of a panel of 52 structurally related chromone derivatives; namely, flavonoids, 2-styrylchromones, 2-styrylchromone-related derivatives [2-(4-arylbuta-1,3-dien-1-yl)chromones], and 4- and 5-styrylpyrazoles against GP, using in silico and in vitro microanalysis screening systems. Several of the tested compounds showed a potent inhibitory effect. The structure–activity relationship study indicated that for 2-styrylchromones and 2-styrylchromone-related derivatives, the hydroxylations at the A and B rings, and in the flavonoid family, as well as the hydroxylation of the A ring, were determinants for the inhibitory activity. To support the in vitro experimental findings, molecular docking studies were performed, revealing clear hydrogen bonding patterns that favored the inhibitory effects of flavonoids, 2-styrylchromones, and 2-styrylchromone-related derivatives. Interestingly, the potency of the most active compounds increased almost four-fold when the concentration of glucose increased, presenting an IC50 < 10 µM. This effect may reduce the risk of hypoglycemia, a commonly reported side effect of antidiabetic agents. This work contributes with important considerations and provides a better understanding of potential scaffolds for the study of novel GP inhibitors.

scholarly journals Quinazolin-4-one derivatives lacking toxicity-producing attributes as glucokinase activators: design, synthesis, molecular docking, and in-silico ADMET prediction

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Saurabh C. Khadse ◽  
Nikhil D. Amnerkar ◽  
Manasi U. Dave ◽  
Deepak K. Lokwani ◽  
Ravindra R. Patil ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Enzyme Assay ◽  
Binding Free Energy ◽  
Docking Studies ◽  
Oral Glucose ◽  
Substitution Pattern ◽  
Glucokinase Activators ◽  
In Silico Admet

Abstract Background A small library of quinazolin-4-one clubbed thiazole acetates/acetamides lacking toxicity-producing functionalities was designed, synthesized, and evaluated for antidiabetic potential as glucokinase activators (GKA). Molecular docking studies were done in the allosteric site of the human glucokinase (PDB ID: 1V4S) enzyme to assess the binding mode and interactions of synthesized hits for best-fit conformations. All the compounds were evaluated by in vitro enzymatic assay for GK activation. Results Data showed that compounds 3 (EC50 = 632 nM) and 4 (EC50 = 516 nM) showed maximum GK activation compared to the standards RO-281675 and piragliatin. Based on the results of the in vitro enzyme assay, docking studies, and substitution pattern, selected compounds were tested for their glucose-lowering effect in vivo by oral glucose tolerance test (OGTT) in normal rats. Compounds 3 (133 mg/dL) and 4 (135 mg/dL) exhibited prominent activity by lowering the glucose level to almost normal, eliciting the results in parallel to enzyme assay and docking studies. Binding free energy, hydrogen bonding, and π–π interactions of most active quinazolin-4-one derivatives 3 and 4 with key amino acid residues of the 1V4S enzyme were studied precisely. Preliminary in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out using SwissADME and PreADMET online software which revealed that all the compounds have the potential to become orally active antidiabetic agents as they obeyed Lipinski's rule of five. Conclusion The results revealed that the designed lead could be significant for the strategic design of safe, effective, and orally bioavailable quinazolinone derivatives as glucokinase activators.

scholarly journals Design, Synthesis and Pharmacological Evaluation of Novel Imidazopyridine Analogues as Proton Pump Antagonist

2020 ◽  
Vol 32 (4) ◽  
pp. 776-782
Author(s):  
Ravindra S. Sonawane ◽  
Kiran D. Patil ◽  
Avinash V. Patil
Keyword(s):  
Spectral Analysis ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Inhibitory Activity ◽  
Positive Control ◽  
Docking Studies ◽  
Design Synthesis ◽  
Standard Drug ◽  
Imidazopyridine Derivatives

A series of novel imidazopyridine derivatives as proton pump inhibitors was designed with compounds of CID data base and explored considering AZD0865 as standard. Many compounds were identified and docked in proton pump ATPase pocket (PDB ID: 4ux2). Molecular docking studies revealed that many compounds showed good proton pump ATPase inhibitory activity. The docking poses revealed the interaction of ligands with amino acid. The standard drug AZD0865 had docking score of -7.112302 and displayed interactions with Asn138 and Asp137. A series of novel imidazopyridine derivatives as proton pump inhibitors were docked, synthesized and characterized by IR, NMR, CHN and MS spectral analysis. The target imidazopyridines were prepared from substituted 2-aminonicotinic acid and 2-bromo-1-substituted ethanone. in vitro Studies explained that few compounds exhibited moderate to good proton pump ATPase inhibitory activity in comparison with the reference drugs i.e. AZD0865. Compounds 11 and 12 shown higher activities with the IC50 4.3. Compounds 1, 4, 6, 7, 8, 10 and 13 showed weak anti-ulcer activity with its IC50 5.2, 5.8, 5.5, 5.1, 4.9, 4.6 and 5.9 and positive control AZD0865 shown IC50 2.0.

2-Mercapto Benzothiazole Derivatives: As Potential Leads for the Diabetic Management

2020 ◽  
Vol 16 (6) ◽  
pp. 826-840
Author(s):  
Saeed Ullah ◽  
Salma Mirza ◽  
Uzma Salar ◽  
Shafqat Hussain ◽  
Kulsoom Javaid ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Inhibitory Activity ◽  
Kinetic Studies ◽  
Binding Pocket ◽  
Docking Studies ◽  
Standard Drug ◽  
Dual Nature ◽  
Benzothiazole Derivatives ◽  
Glucosidase Inhibitors

Background: Results of our previous studies on antiglycation activity, and the noncytotoxicity of 2-mercapto benzothiazoles, encouraged us to further widen our investigation towards the identification of leads against diabetes mellitus. Methods: 33 derivatives of 2-mercapto benzothiazoles 1-33 were evaluated for in vitro α- glucosidase inhibitory activity. Mode of inhibition was deduced by kinetic studies. To predict the interactions of 2-mercapto benzothiazole derivatives 1-33 with the binding pocket of α-glucosidase enzyme, molecular docking studies were performed on the selected inhibitors. Results: Compounds 2-4, 6-7, 9-26, 28 and 30 showed many folds potent α-glucosidase inhibitory activity in the range of IC50 = 31.21-208.63 μM, as compared to the standard drug acarbose (IC50 = 875.75 ± 2.08 μM). It was important to note that except derivative 28, all other derivatives were also found previously to have antiglycating potential in the range of IC50 = 187.12-707.21 μM. Conclusion: A number of compounds were identified as dual nature as antiglycating agent and α- glucosidase inhibitors. These compounds may serve as potential lead candidates for the management of diabetes mellitus.

Exploration of Diosmin to control diabitis and its complications-an in vitro and in silico approach

2020 ◽  
Vol 16 ◽  
Author(s):  
Kushagra Dubey ◽  
Raghvendra Dubey ◽  
Revathi Gupta ◽  
Arun Gupta
Keyword(s):  
Molecular Docking ◽  
Aldose Reductase ◽  
Inhibitory Activity ◽  
Blood Lipid ◽  
Docking Studies ◽  
Alpha Amylase ◽  
Lipid Lowering ◽  
Molecular Docking Studies ◽  
Alpha Glucosidase

Background: Diosmin is a flavonoid obtained from the citrus fruits of the plants. Diosmin has blood lipid lowering activities, antioxidant activity, enhances venous tone and microcirculation, protects capillaries, mainly by reducing systemic oxidative stress. Objective: The present study demonstrates the potential of Diosmin against the enzymes aldose reductase, α-glucosidase, and α-amylase involved in diabetes and its complications by in vitro evaluation and reverse molecular docking studies. Method: The assay of aldose reductase was performed by using NADPH as starting material and DL-Glyceraldehyde as a substrate. DNS method was used for alpha amylase inhibition and in alpha glucosidase inhibitory activity p-nitrophenyl glucopyranoside (pNPG) was used as substrate. The reverse molecular docking studies was performed by using Molegro software (MVD) with grid resolution of 30 Å. Result: Diosmin shows potent inhibitory effect against aldose reductase (IC50:333.88±0.04 µg/mL), α-glucosidase (IC50:410.3±0.01 µg/mL) and α-amylase (IC50: 404.22±0.02 µg/mL) respectively. The standard drugs shows moderate inhibitory activity for enzymes. The MolDock Score of Diosmin was -224.127 against aldose reductase, -168.17 against α-glucosidase and -176.013 against α-amylase respectively, which was much higher than standard drugs. Conclusion: From the result it was concluded that diosmin was a potentially inhibitor of aldose reductase, alpha amylase and alpha glucosidase enzymes then the standard drugs and it will be helpful in the management of diabetes and its complications. This will also be benevolent to decrease the socio economical burden on the middle class family of the society.

scholarly journals Structure Related α-Glucosidase Inhibitory Activity and Molecular Docking Analyses of Phenolic Compounds From Paeonia Suffruticosa

2021 ◽  
Author(s):  
Po-Chun Chen ◽  
Bongani Sicelo Dlamini ◽  
Chiy-Rong Chen ◽  
Yueh-Hsiung Kuo ◽  
Wen-Ling Shih ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Phenolic Compounds ◽  
Inhibitory Activity ◽  
Inhibitory Effect ◽  
Docking Studies ◽  
Inhibition Mechanism ◽  
Root Bark ◽  
Paeonia Suffruticosa ◽  
Glucosidase Inhibitors

Abstract In the continuous search for α-glucosidase inhibitors, eleven phenolic compounds (1-11) were isolated from the root bark of Paeonia suffruticosa. Their α-glucosidase inhibitory activity and inhibition mechanism were investigated using an in vitro inhibition assay and molecular docking studies. Compounds 2, 5, 6, and 8-11 (IC50 between 290 and 431 µM) inhibited α-glucosidase more effectively than the reference compound acarbose (IC50=1463 ± 29.5 µM). Among them, compound 10 exhibited the highest α-glucosidase inhibitory effect with an IC50 value of 290.4 ± 9.6 µM. Compounds 2, 5, 9 10 and 11 were found to be competitive inhibitors, while compounds 6 and 8 were noncompetitive inhibitors of α-glucosidase. Computational analyses showed that the main binding forces between the compounds and the main residues were hydrogen bonds. The results indicated that these compounds had considerable α-glucosidase inhibitory activity.

scholarly journals Discovery of a Natural Syk Inhibitor from Chinese Medicine through a Docking-Based Virtual Screening and Biological Assay Study

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3114
Author(s):  
Xing Wang ◽  
Junfang Guo ◽  
Zhongqi Ning ◽  
Xia Wu
Keyword(s):  
Mast Cell ◽  
Chinese Medicine ◽  
Virtual Screening ◽  
Inhibitory Activity ◽  
Docking Studies ◽  
Mast Cell Degranulation ◽  
Amino Acid Residues ◽  
Tanshinone I ◽  
Syk Inhibitor

Spleen tyrosine kinase (Syk) is a critical target protein for treating immunoreceptor signalling-mediated allergies. In this study, a virtual screening of an in-house Chinese medicine database followed by biological assays was carried out to identify novel Syk inhibitors. A molecular docking method was employed to screen for compounds with potential Syk inhibitory activity. Then, an in vitro kinase inhibition assay was performed to verify the Syk inhibitory activity of the virtual screening hits. Subsequently, a β-hexosaminidase release assay was conducted to evaluate the anti-mast cell degranulation activity of the active compounds. Finally, tanshinone I was confirmed as a Syk inhibitor (IC50 = 1.64 μM) and exhibited anti-mast cell degranulation activity in vitro (IC50 = 2.76 μM). Docking studies showed that Pro455, Gln462, Leu377, and Lys458 were key amino acid residues for Syk inhibitory activity. This study demonstrated that tanshinone I is a Syk inhibitor with mast cell degranulation inhibitory activity. Tanshinone I may be a potential lead compound for developing effective and safe Syk-inhibiting drugs.

scholarly journals In silico docking studies and in vitro xanthine oxidase inhibitory activity of commercially available terpenoids

2012 ◽  
Vol 2 (5) ◽  
Author(s):  
MUTHUSWAMY UMAMAHESWARI ◽  
Preetha Prabhu ◽  
KUPPUSAMY ASOKKUMAR ◽  
THIRUMALAISAMY SIVASHANMUGAM ◽  
Varadharajan Subhadradevi ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Docking Studies ◽  
In Silico Docking

In vitro Acetylcholinesterase inhibitory activity of polyphenolic compounds identified from Matricaria recutita

2020 ◽  
Vol 19 (08) ◽  
pp. 2050029
Author(s):  
Suhailah Wasman Qader ◽  
Hassan H. Abdallah ◽  
Mstaffa Zahid ◽  
Lee Suan Chua
Keyword(s):  
Inhibitory Activity ◽  
Ultra Performance Liquid Chromatography ◽  
Docking Studies ◽  
Cognitive Disorder ◽  
Polyphenolic Compounds ◽  
Accurate Analysis ◽  
Matricaria Recutita ◽  
Key Enzyme

Acetylcholinesterase (AChE) is a key enzyme enhancing the cognitive disorder, leading to Alzheimer’s disease, and AChE inhibition is a crucial therapeutic mechanism against it. Matricaria recutita (MR) is widely used as a herbal medicine due to its phytotherapeutic properties. For this reason, MR flower was evaluated to identify polyphenolic compounds (PC), and then each PC is examined for AChE inhibitory activity. The ultra-performance liquid chromatography-electrospray tandem mass spectrometry UPLC-ESI-MS/MS was used to detect PC, and molecular docking was performed to insight potential inhibitory activity of PC against AChE. A series of 13 PC compounds were identified in the fractions of MR plant. Docking studies revealed that the inhibitory free energy and the position of the docked compounds in the active site are favored for the active compounds complex formed between AChE and the identified PC compounds. The accurate analysis of the docking result demonstrates that Kaempferol-3-O-rutinoside (KR) and Luteolin-8-C-glucoside (orientin) (LG) are the most significant inhibitory compounds against AChE. It can be concluded that MR is a significant source of PC compounds, and KR and LG are the most promising compounds that have high-affinity binding to AChE, based on docking outcome. Further experiments are recommended to explore in vivo enzyme compound interaction and toxicity models to establish the maximum suggested dose.

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