scholarly journals Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 799
Author(s):  
Elix Alberto Domínguez-Mendoza ◽  
Yelzyn Galván-Ciprés ◽  
Josué Martínez-Miranda ◽  
Cristian Miranda-González ◽  
Blanca Colín-Lozano ◽  
...  
Keyword(s):  
In Silico ◽  
Molecular Design ◽  
Tyrosine Phosphatase ◽  
Binding Pocket ◽  
Binding Mode ◽  
Antidiabetic Activity ◽  
Design Synthesis ◽  
Consensus Analysis ◽  
Glucose Levels

Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.

scholarly journals Design, Synthesis, Antihyperglycemic Studies, and Docking Simulations of Benzimidazole-Thiazolidinedione Hybrids

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Abraham Gutierréz-Hernández ◽  
Yelzyn Galván-Ciprés ◽  
Elix Alberto Domínguez-Mendoza ◽  
Yoshajandith Aguirre-Vidal ◽  
Samuel Estrada-Soto ◽  
...  
Keyword(s):  
Mrna Expression ◽  
In Silico ◽  
Knoevenagel Condensation ◽  
Binding Mode ◽  
Spectral Studies ◽  
Design Synthesis ◽  
Docking Simulations ◽  
Step Procedure

A simple and cheap three-step procedure for the synthesis of three (5Z)-5-[3(4)-(1H-benzimidazol-2-ylmethoxy)benzylidene]-1,3-thiazolidine-2,4-diones has been described via a SN2 reaction of generally recognized as safe hydroxybenzaldehydes and 2-(chloromethyl)-1H-benzimidazole, followed by a Knoevenagel condensation with thiazolidine-2,4-dione in moderated yields. All the newly synthesized compounds were characterized using analytical and spectral studies. In vitro treatment on adipocytes with compounds increased the mRNA expression of two proteins recognized as strategic targets in diabetes: PPARγ and GLUT-4. In silico studies were conducted in order to explain the interaction binding mode of the synthesized compounds on PPARγ. In vivo studies confirmed that compounds 1–3 have robust antihyperglycemic action linked to insulin sensitization mechanisms. The present study provides three compounds with a promising antidiabetic action.

scholarly journals Synthesis and In Vitro AMPK Activation of Cycloalkyl/Alkarylbiguanides with Robust In Vivo Antihyperglycemic Action

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Erika Gutierrez-Lara ◽  
Carlos Martínez-Conde ◽  
Edgar Rosales-Ortega ◽  
Juan José Ramírez-Espinosa ◽  
Julio C. Rivera-Leyva ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Tolerance Test ◽  
Regulatory Subunit ◽  
Oral Glucose ◽  
Alkyl Aryl ◽  
Design Synthesis ◽  
Glucose Levels ◽  
Amp Activated Protein Kinase

This work describes the design, synthesis in one step, and the in vitro, in vivo, and in silico antidiabetic evaluation of a series of ten alicyclic and aromatic (alkyl +aryl: alkaryl)biguanides, analogues of metformin and phenformin. The design was conceived using isosteric replacement, chain-ring transformation, and lower and higher homologation strategies. All compounds were obtained as crystals and their structure was confirmed on the basis of their spectral data (NMR and mass spectra), and their purity was ascertained by microanalysis. Compounds were in vitro evaluated as activators of AMP-Activated Protein Kinase (AMPK). The results indicated that compounds 4, 5, and 6 showed similar or even better effect compared to metformin. Docking analysis was performed with regulatory subunit γ of AMPK, showing several interactions with nucleotide binding pocket. The in vivo evaluation of compounds 4–6 at a single dose of 50 mg/kg was performed in a murine experimental model of diabetes. The results showed an important and robust decrease of plasmatic glucose levels (−40%). Compound 6 was selected for an oral glucose tolerance test, showing an antihyperglycemic effect similar to metformin. The in vivo results indicated that compounds 4–6 may be effective in treating experimental T2DM.

scholarly journals In-Vivo Antidiabetic Activity and In-Silico Mode of Action of LC/MS-MS Identified Flavonoids in Oleaster Leaves

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5073 ◽  
Author(s):  
Hamza Mechchate ◽  
Imane Es-Safi ◽  
Mohammed Bourhia ◽  
Andrii Kyrylchuk ◽  
Abdelfattah El Moussaoui ◽  
...  
Keyword(s):  
Mode Of Action ◽  
In Silico ◽  
Diabetes Management ◽  
Tyrosine Phosphatase ◽  
Olive Tree ◽  
Bioactive Molecules ◽  
Antidiabetic Activity ◽  
Dipeptidyl Peptidase 4 ◽  
Olea Europea

Background: Olea europea L. subsp. europaea var. sylvestris (Mill) Lehr (Oleaster) is a wild endemic olive tree indigenous to the Mediterranean region. Olea europea leaves represent a natural reservoir of bioactive molecules that can be used for therapeutic purposes. Aim of the study: This work was conducted to study antidiabetic and antihyperglycemic activities of flavonoids from oleaster leaves using alloxan-induced diabetic mice. The mode of action of flavonoids against eight receptors that have a high impact on diabetes management and complication was also investigated using molecular docking. Results: During 28 days of mice treatment with doses 25 and 50 mg/kg b.w, the studied flavonoids managed a severe diabetic state (<450 mg/dL), exhibiting a spectacular antidiabetic and antihyperglycemic activity, and improved mice health status compared to diabetic control. The in-silico mode of action of oleaster flavonoids revealed the inhibition of protein tyrosine phosphatase 1B (PTP1B), Dipeptidyl-peptidase 4 (DPP4), α-Amylase (AAM), α-Glucosidase inhibition, Aldose reductase (AldR), Glycogen phosphorylase (GP), and the activation of free fatty acid receptor 1 (FFAR1). Conclusion: The findings obtained in the present work indicate that the flavonoids from the oleaster may constitute a safe multi-target remedy to treat diabetes.

scholarly journals Design, synthesis and anti-diabetic activity of some novel xanthone derivatives targeting α-glucosidase

2016 ◽  
Vol 11 (2) ◽  
pp. 308 ◽  
Author(s):  
Partha Sarathi Bairy ◽  
Aparoop Das ◽  
Lalit Mohan Nainwal ◽  
Tapan Kumar Mohanta ◽  
Mukesh Kumar Kumawat ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Video Clip ◽  
Diabetic Animal ◽  
Antidiabetic Activity ◽  
Spectroscopic Techniques ◽  
Design Synthesis ◽  
Standard Drug ◽  
Glucose Levels ◽  
Xanthone Derivatives

<p>Twenty eight xanthone derivatives were designed and docked into the N-terminal catalytic domain of maltase-glucoamylase (ntMGAM) by considering Miglitol as standard drug. Most of the molecules showed excellent docking scores and docking interaction as compared to the binding cavity of the standard molecule. The five best scoring ligands were synthesized and characterized by a number of analytical and spectroscopic techniques. The molecules were screened for the <em>in vivo</em> antidiabetic activity in streptozotocin (STZ) induced diabetic animal model in Wistar rats. Compound P4 showed the most prominent inhibition among others. The synthesized compounds reported significant (p&lt; 0.01) effect of lowering glucose levels in the blood compared to miglitol as a standard α-glucosidase inhibitor.</p><p><strong>Video clip</strong></p><p>Induction of diabetes: </p>

Development of Novel Glitazones as Antidiabetic Agents: Molecular Design, Synthesis, Evaluation of Glucose Uptake Activity and SAR Studies

2020 ◽  
Vol 17 (7) ◽  
pp. 840-849
Author(s):  
Mahendra Gowdru Srinivas ◽  
Prabitha Prabhakaran ◽  
Subhankar Probhat Mandal ◽  
Yuvaraj Sivamani ◽  
Pranesh Guddur ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Molecular Design ◽  
Docking Studies ◽  
Antidiabetic Activity ◽  
Design Synthesis ◽  
In Silico Docking ◽  
Ppar Γ ◽  
Sar Studies ◽  
Structure Activity ◽  
Uptake Activity

Background: Thiazolidinediones and its bioisostere, namely, rhodanines have become ubiquitous class of heterocyclic compounds in drug design and discovery. In the present study, as part of molecular design, a series of novel glitazones that are feasible to synthesize in our laboratory were subjected to docking studies against PPAR-γ receptor for their selection. Methods and Results: As part of the synthesis of selected twelve glitazones, the core moiety, pyridine incorporated rhodanine was synthesized via dithiocarbamate. Later, a series of glitazones were prepared via Knovenageal condensation. In silico docking studies were performed against PPARγ protein (2PRG). The titled compounds were investigated for their cytotoxic activity against 3T3-L1 cells to identify the cytotoxicity window of the glitazones. Further, within the cytotoxicity window, glitazones were screened for glucose uptake activity against L6 cells to assess their possible antidiabetic activity. Conclusion: Based on the glucose uptake results, structure activity relationships are drawn for the title compounds.

scholarly journals Exploring aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction: an in silico study

2021 ◽  
Author(s):  
Chiara Luise ◽  
Dina Robaa ◽  
Wolfgang Sippl
Keyword(s):  
Molecular Dynamic ◽  
In Silico ◽  
Binding Pocket ◽  
Binding Mode ◽  
Molecular Dynamic Simulations ◽  
Flexible Docking ◽  
Dynamic Simulations ◽  
Binding Mode Prediction ◽  
Aromatic Cage ◽  
The Right

AbstractSome of the main challenges faced in drug discovery are pocket flexibility and binding mode prediction. In this work, we explored the aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction by means of in silico approaches. We first investigated the Spindlin1 aromatic cage plasticity by analyzing the available crystal structures and through molecular dynamic simulations. Then we assessed the ability of rigid docking and flexible docking to rightly reproduce the binding mode of a known ligand into Spindlin1, as an example of a reader protein displaying flexibility in the binding pocket. The ability of induced fit docking was further probed to test if the right ligand binding mode could be obtained through flexible docking regardless of the initial protein conformation. Finally, the stability of generated docking poses was verified by molecular dynamic simulations. Accurate binding mode prediction was obtained showing that the herein reported approach is a highly promising combination of in silico methods able to rightly predict the binding mode of small molecule ligands in flexible binding pockets, such as those observed in some reader proteins.

scholarly journals Antidiabetic activity of some pentacyclic acid triterpenoids, role of PTP–1B: In vitro, in silico, and in vivo approaches

2011 ◽  
Vol 46 (6) ◽  
pp. 2243-2251 ◽  
Author(s):  
Juan José Ramírez-Espinosa ◽  
Maria Yolanda Rios ◽  
Sugey López-Martínez ◽  
Fabian López-Vallejo ◽  
José L. Medina-Franco ◽  
...  
Keyword(s):  
In Silico ◽  
Antidiabetic Activity ◽  
Ptp 1B

N-pyridin-2-yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro,in silico and in vivo evaluation

2018 ◽  
Vol 93 (3) ◽  
pp. 364-372 ◽  
Author(s):  
Ajmer Singh Grewal ◽  
Rajeev Kharb ◽  
Deo Nandan Prasad ◽  
Jagdeep Singh Dua ◽  
Viney Lather
Keyword(s):  
In Silico ◽  
In Vivo Evaluation ◽  
Design Synthesis

Design, synthesis, in-vitro, in-vivo and in-silico studies of pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents

2020 ◽  
Vol 186 ◽  
pp. 111863 ◽  
Author(s):  
Muhammad Saeed Jan ◽  
Sajjad Ahmad ◽  
Fida Hussain ◽  
Ashfaq Ahmad ◽  
Fawad Mahmood ◽  
...  
Keyword(s):  
In Silico ◽  
Design Synthesis ◽  
In Silico Studies ◽  
Anti Inflammatory
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