Molecular Modeling and Computer-Designing for New Compounds Starting From Thiazolidinedione Molecule as Anti-Hyperglycemics

2021 ◽  
Vol 14 (1) ◽  
pp. 5271-5277
Author(s):  
Mohamad Yahia Shikh Awad
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Docking Study ◽  
Test Set ◽  
Diabetic Type ◽  
Discovery Studio ◽  
Ppar Γ ◽  
Computer Designing ◽  
New Compounds

In the quest for novel PPAR-γ agonists as putative drugs  for the treatment of type 2 diabetes, a new test set  molecules were proposed as bioisosteric analogues to  the anti-diabetic thiazolidine-2, 5-diones (TZDs). Virtual  screening fitting study of these new molecules with the  generated discovery studio (DS) common feature PPAR-γ  agonist's hypothesis has predicted that most of these are  active as PPAR-γ agonist and hence they are as  antidiabetic-type 2 agents. Furthermore, molecular  docking virtual screening for these active compounds, with the binding site of the PPAR-γ enzyme, revealed that  the 2-pyrazolin-5-one and pyrazolidine-3,5-dione  derivatives have higher or similar docking scores like that  of the rosiglitazone. Also, the same docking study  revealed that these compounds have the same binding  site. This predicted that the designed proposed new  molecules are considered PPAR-γ agonists active, and  hence they are recommended to be synthesized as  potential anti-diabetic type-2 agents.  

A New Reactive Ketenaminal: Synthesis, Coupling Reaction, Tautomeric Study, Docking and Antimicrobial Evaluation of the Products

2020 ◽  
Vol 16 (6) ◽  
pp. 761-773
Author(s):  
Huda K. Mahmoud ◽  
Hanadi A. Katouah ◽  
Marwa F. Harras ◽  
Thoraya A. Farghaly
Keyword(s):  
Binding Site ◽  
Antimicrobial Agents ◽  
Coupling Reaction ◽  
Docking Study ◽  
Binding Mode ◽  
Binding Energies ◽  
Simple Method ◽  
Antimicrobial Evaluation ◽  
New Compounds ◽  
Active Methylene

Background: One of the most successful reagents used in the synthesis of the reactive enaminone is DMF-DMA, but it is very expensive with harmful effects on the human health and reacts with special compounds to generate the enaminone such as active methylene centers. Aim: In this article, we synthesized a new ketenaminal by simple method with inexpensive reagents (through desulfurization in diphenylether). Methods: Thus, a novel reactive ketenaminal (enaminone) was synthesized from the desulfurization of 2-((2-(4-chlorophenyl)-2-oxoethyl)thio)-5,7-bis(4-methoxyphenyl)pyrido[2,3-d]pyrimidin- 4(3H)-one with diphenylether. The starting keteneaminal was coupled with diazotized anilines via the known coupling conditions to give a new series of 2-(4-chlorophenyl)-1-(2-(arylhydrazono)-2- oxoethyl)-5,7-bis(4-methoxy-phenyl)pyrido[2,3-d]pyrimidin-4(1H)-ones. Results: The structures of the new compounds were elucidated based on their IR, 1H-NMR, 13CNMR, and Mass spectra. Moreover, the potency of these compounds as antimicrobial agents has been evaluated. The results showed that some of the products have high activity nearly equal to that of the used standard antibiotic. Additionally, the docking study was done to get the binding mode of the synthesized compounds with the binding site of the DHFR enzyme. The results of molecular docking of the synthesized arylhydrazono compounds are able to fit in DHFR binding site with binding energies ranging from -4.989 to -8.178 Kcal/mol. Conclusion: Our goal was achieved in this context by the synthesis of new ketenaminal from inexpensive reagents, which was utilized in the preparation of bioactive arylhydrazone derivatives.

scholarly journals Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening

2014 ◽  
Vol 2014 ◽  
pp. 1-21 ◽  
Author(s):  
Shikhar Gupta ◽  
C. Gopi Mohan
Keyword(s):  
Molecular Docking ◽  
Binding Site ◽  
Enzyme Inhibitors ◽  
Acetylcholinesterase Inhibitors ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Test Set ◽  
Zinc Database ◽  
Pharmacophore Hypotheses ◽  
Pharmacophore Models

In this study, we have employedin silicomethodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer’s randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties.

scholarly journals In-silico Approach for The Prediction of Chlorogenic Acid as PPAR-γ Activator

Biota ◽  
2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Yohanes Bare ◽  
Mansur S ◽  
Sukarman Hadi Jaya Putra ◽  
Margaretha Rika W G L ◽  
Dewi Ratih Tirto Sari
Keyword(s):  
Physicochemical Properties ◽  
Chlorogenic Acid ◽  
Peroxisome Proliferator ◽  
Amino Acid Residues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Discovery Studio ◽  
Ppar Γ ◽  
Pubchem Database

Coffee is one of the essential crops commonly cultivated in Indonesia. Coffee contains diverse bioactive compounds, which are associated with human health benefits. One of the compounds is Chlorogenic acid, which able to decrease the risk of type 2 diabetes mellitus (T2DM). However, the mechanism of chlorogenic acid toward anti-diabetes still unclear. This study aimed to analyze and investigate the potential role of chlorogenic acid as anti-diabetes through their interaction with Peroxisome proliferator-activated receptor gamma (PPAR-γ) as an enzyme to phosphorylate and regulate the mechanism of T2DM. The physicochemical properties of chlorogenic acid also performed in this study. The PPAR-γ was downloaded from the PDB database, and the chlorogenic acid was retrieved from the PubChem database. The protein and ligand were prepared using the PyRx program and were docked using Hex 8.0.0 software. Discovery Studio client 4.1 software was used to analyze the interaction between chlorogenic acid and PPAR-γ protein. Based on the physicochemical properties, chlorogenic acid is highly permeable to the cell and easily absorbed.  Thirteen amino acid residues of PPAR-γ (GLN410, SER394, ASP396, GLY395, GLU407, LEUA401, LEU400, VAL403, LYS373, LYS438, LEU377, LYS434, and GLY437) were identified on the chlorogenic acid-PPAR-γ interaction. Interestingly, the kind of interactions, including hydrophobic interaction, hydrogen bond, and van der Waals, which are supported by the tight interaction. Our study indicated that chlorogenic acid might have anti-diabetes activity through PPAR-γ interaction.  

Comprehensive in silico Study of GLUT10: Prediction of Possible Substrate Binding Sites and Interacting Molecules

2020 ◽  
Vol 21 (2) ◽  
pp. 117-130 ◽  
Author(s):  
Mohammad J. Hosen ◽  
Mahmudul Hasan ◽  
Sourav Chakraborty ◽  
Ruhshan A. Abir ◽  
Abdullah Zubaer ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Glucose Transporter ◽  
Substrate Binding ◽  
Mutation Screening ◽  
Homology Model ◽  
Connective Tissue Disorder ◽  
Crystallographic Structure ◽  
Substrate Binding Site

Objectives: The Arterial Tortuosity Syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and stenosis of the arteries with a propensity towards aneurysm formation and dissection. It is caused by mutations in the SLC2A10 gene that encodes the facilitative glucose transporter GLUT10. The molecules transported by and interacting with GLUT10 have still not been unambiguously identified. Hence, the study attempts to identify both the substrate binding site of GLUT10 and the molecules interacting with this site. Methods: As High-resolution X-ray crystallographic structure of GLUT10 was not available, 3D homology model of GLUT10 in open conformation was constructed. Further, molecular docking and bioinformatics investigation were employed. Results and Discussion: Blind docking of nine reported potential in vitro substrates with this 3D homology model revealed that substrate binding site is possibly made with PRO531, GLU507, GLU437, TRP432, ALA506, LEU519, LEU505, LEU433, GLN525, GLN510, LYS372, LYS373, SER520, SER124, SER533, SER504, SER436 amino acid residues. Virtual screening of all metabolites from the Human Serum Metabolome Database and muscle metabolites from Human Metabolite Database (HMDB) against the GLUT10 revealed possible substrates and interacting molecules for GLUT10, which were found to be involved directly or partially in ATS progression or different arterial disorders. Reported mutation screening revealed that a highly emergent point mutation (c. 1309G>A, p. Glu437Lys) is located in the predicted substrate binding site region. Conclusion: Virtual screening expands the possibility to explore more compounds that can interact with GLUT10 and may aid in understanding the mechanisms leading to ATS.

Novel coumarin containing dithiocarbamate derivatives as potent α-glucosidase inhibitors for management of type 2 diabetes

2020 ◽  
Vol 16 ◽  
Author(s):  
Marjan Mollazadeh ◽  
Maryam Mohammadi-Khanaposhtani ◽  
Yousef Valizadeh ◽  
Afsaneh Zonouzi ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kinetic Study ◽  
Active Site ◽  
Docking Study ◽  
Secondary Amines ◽  
Molecular Docking Study ◽  
Glucosidase Inhibitors ◽  
Dithiocarbamate Derivatives

Background: α-Glucosidase is a hydrolyze enzyme that plays a crucial role in degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in the carbohydrate mediated diseases such as diabetes mellitus. Objective: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. Methods: These compounds were obtained of reaction between 4-(bromomethyl)-7-methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). Results: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 μM) in comparison to acarbose as standard inhibitor (IC50 = 750.0 ± 9.0 µM). Among them, secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound compete with substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Also, molecular docking study predicted that this compound as well interacted with α-glucosidase active site pocket. Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for design potent α-glucosidase inhibitors for treatment of type 2 diabetes.

scholarly journals Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells

2021 ◽  
Vol 14 (1) ◽  
pp. 49
Author(s):  
David Méndez-Luna ◽  
Loreley Araceli Morelos-Garnica ◽  
Juan Benjamín García-Vázquez ◽  
Martiniano Bello ◽  
Itzia Irene Padilla-Martínez ◽  
...  
Keyword(s):  
Binding Site ◽  
Cell Lines ◽  
Cancer Cell ◽  
Inhibitory Activity ◽  
In Silico ◽  
Cancer Cell Lines ◽  
Pancreatic Cancer Cells ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
New Compounds

The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines—MIA Paca-2, RCC4-VA and Hep G2—at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models.

scholarly journals High Energy Intake Induced Overexpression of Transcription Factors and Its Regulatory Genes Involved in Acceleration of Hepatic Lipogenesis: A Rat Model for Type 2 Diabetes

Biomedicines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 76 ◽  
Author(s):  
Suresh P. Khadke ◽  
Aniket A. Kuvalekar ◽  
Abhay M. Harsulkar ◽  
Nitin Mantri
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factors ◽  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
High Energy ◽  
Tolerance Test ◽  
Diabetic Control ◽  
Ppar Γ

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by impaired insulin action and its secretion. The objectives of the present study were to establish an economical and efficient animal model, mimicking pathophysiology of human T2DM to understand probable molecular mechanisms in context with lipid metabolism. In the present study, male Wistar rats were randomly divided into three groups. Animals were fed with high fat diet (HFD) except healthy control (HC) for 12 weeks. After eight weeks, intra peritoneal glucose tolerance test was performed. After confirmation of glucose intolerance, diabetic control (DC) group was injected with streptozotocin (STZ) (35 mg/kg b.w., i.p.). HFD fed rats showed increase (p ≤ 0.001) in glucose tolerance and HOMA-IR as compared to HC. Diabetes rats showed abnormal (p ≤ 0.001) lipid profile as compared to HC. The hepatocyte expression of transcription factors SREBP-1c and NFκβ, and their target genes were found to be upregulated, while PPAR-γ, CPT1A and FABP expressions were downregulated as compared to the HC. A number of animal models have been raised for studying T2DM, but the study has been restricted to only the biochemical level. The model is validated at biochemical, molecular and histopathological levels, which can be used for screening new therapeutics for the effective management of T2DM.

P36 Aldosterone protects the insulin-activated AKT pathway in heart of diabetic type 2 mice

2012 ◽  
Vol 38 ◽  
pp. A40
Author(s):  
L. Fazal ◽  
F. Azibani ◽  
N. Bihry ◽  
R. Merval ◽  
E. Polidano ◽  
...  
Keyword(s):  
Akt Pathway ◽  
Diabetic Type
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