scholarly journals GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6283 ◽  
Author(s):  
Sadia Zafar ◽  
Ishrat Jabeen
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Molecular Descriptor ◽  
Biological Membrane ◽  
Ion Homeostasis ◽  
Aminobutyric Acid ◽  
Structural Basis ◽  
Cooh Group ◽  
Data Series ◽  
Gaba Transport

BackgroundThe γ-aminobutyric acid (GABA) transporter GAT1 is involved in GABA transport across the biological membrane in and out of the synaptic cleft. The efficiency of this Na+coupled GABA transport is regulated by an electrochemical gradient, which is directed inward under normal conditions. However, in certain pathophysiological situations, including strong depolarization or an imbalance in ion homeostasis, the GABA influx into the cytoplasm is increased by re-uptake transport mechanism. This mechanism may lead to extra removal of extracellular GABA which results in numerous neurological disorders such as epilepsy. Thus, small molecule inhibitors of GABA re-uptake may enhance GABA activity at the synaptic clefts.MethodsIn the present study, various GRID-independent molecular descriptor (GRIND) models have been developed to shed light on the 3D structural features of human GAT1 (hGAT1) inhibitors using nipecotic acid and N-diarylalkenyl piperidine analogs. Further, a binding hypothesis has been developed for the selected GAT1 antagonists by molecular docking inside the binding cavity of hGAT1 homology model.ResultsOur results indicate that two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic region at certain distances from each other play an important role in achieving high inhibitory potency against hGAT1. Our docking results elucidate the importance of the COOH group in hGAT1 antagonists by considering substitution of the COOH group with an isoxazol ring in compound37, which subsequently leads to a three order of magnitude decrease in biological activity of37(IC50= 38 µM) as compared to compound1(IC50= 0.040 µM).DiscussionOur docking results are strengthened by the structure activity relationship of the data series as well as by GRIND models, thus providing a significant structural basis for understanding the binding of antagonists, which may be useful for guiding the design of hGAT1 inhibitors.

scholarly journals Di-μ-chlorido-bis[(2,2′-bipyridine-5,5′-dicarboxylic acid-κ2N,N′)chloridocopper(II)] dimethylformamide tetrasolvate

2013 ◽  
Vol 69 (2) ◽  
pp. m73-m74 ◽  
Author(s):  
Sigurd Øien ◽  
David Stephen Wragg ◽  
Karl Petter Lillerud ◽  
Mats Tilset
Keyword(s):  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Title Compound ◽  
Cooh Group ◽  
Stacking Interactions ◽  
Coordination Geometry ◽  
Complex Molecules ◽  
Centroid Distance ◽  
Solvent Molecules ◽  
Hydrogen Bonded

In the title compound, [Cu2Cl4(C12H8N2O4)2]·4C3H7NO, which contains a chloride-bridged centrosymmetric CuIIdimer, the CuIIatom is in a distorted square-pyramidal 4 + 1 coordination geometry defined by the N atoms of the chelating 2,2′-bipyridine ligand, a terminal chloride and two bridging chloride ligands. Of the two independent dimethylformamide molecules, one is hydrogen bonded to a single –COOH group, while one links two adjacent –COOH groupsviaa strong accepted O—H...O and a weak donated C(O)—H...O hydrogen bond. Two of these last molecules and the two –COOH groups form a centrosymmetric hydrogen-bonded ring in which the CH=O and the –COOH groups by disorder adopt two alternate orientations in a 0.44:0.56 ratio. These hydrogen bonds link the CuIIcomplex molecules and the dimethylformamide solvent molecules into infinite chains along [-111]. Slipped π–π stacking interactions between two centrosymmetric pyridine rings (centroid–centroid distance = 3.63 Å) contribute to the coherence of the structure along [0-11].

scholarly journals DESIGN AND SYNTHESIS OF SOME NEWER IMIDAZOLYL HETEROCYCLES AS POTENT BTK INHIBITORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

2017 ◽  
Vol 9 (3) ◽  
pp. 80
Author(s):  
R. Priyadarsini ◽  
Anandhan Menaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Hydrogen Bond ◽  
Molecular Docking ◽  
Tyrosine Kinase ◽  
Pharmacophore Model ◽  
Spectral Studies ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Hydrogen Bond Acceptor ◽  
Btk Inhibitors

Objective: The rheumatoid arthritis as a global health problem over the past few decades, Emphasizes the need for discovery of new therapeutic disease modifying anti-rheumatoid Arthritis drugs (DMARD’s). Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor, tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in the development, differentiation and proliferation of B-lineage cells, thus making BTK an efficient therapeutic target for the treatment of rheumatoid arthritis. This prompted us to synthesise a novel series of Imidazolyl Heterocycles as potent BTK (Bruton’s Tyrosine Kinase) inhibitors with alleged Anti-Rheumatoid Arthritis properties. Methods: Newer BTK inhibitors containing one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) and three hydrophobic features based on that pharmacophore model for BTK were designed. The designed compounds were sorted by applying ADMET properties, Lipinski rule of five, molecular docking and Novelty prediction to refine the designed ligands. Finally, different five compounds containing Imidazole as the heterocyclic nucleus have been synthesized and characterized by different analytical methods like Chromatographic data, Elemental analysis and Spectral studies by IR, 1H NMR, 13C NMR, GC-MS. Molecular docking studies were performed against BTK using GLIDE 10.2. Results: Several important hydrogen bonds with BTK were revealed, which include the gatekeeper residue Glu475 and Met477 at the hinge region. Conclusion: Overall, this study suggests that the proposed ligands are found to be more effective BTK inhibitor as Anti-Rheumatoid arthritis agents.

scholarly journals Binding Efficacy and Thermogenic Efficiency of Pungent and Nonpungent Analogs of Capsaicin

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3198 ◽  
Author(s):  
Padmamalini Baskaran ◽  
Kyle Covington ◽  
Jane Bennis ◽  
Adithya Mohandass ◽  
Teresa Lehmann ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Docking Studies ◽  
Transient Receptor Potential Vanilloid ◽  
Metabolic Dysfunction ◽  
High Fat

(1) Background: Capsaicin, a chief ingredient of natural chili peppers, enhances metabolism and energy expenditure and stimulates the browning of white adipose tissue (WAT) and brown fat activation to counter diet-induced obesity. Although capsaicin and its nonpungent analogs are shown to enhance energy expenditure, their efficiency to bind to and activate their receptor—transient receptor potential vanilloid subfamily 1 (TRPV1)—to mediate thermogenic effects remains unclear. (2) Methods: We analyzed the binding efficiency of capsaicin analogs by molecular docking. We fed wild type mice a normal chow or high fat diet (± 0.01% pungent or nonpungent capsaicin analog) and isolated inguinal WAT to analyze the expression of thermogenic genes and proteins. (3) Results: Capsaicin, but not its nonpungent analogs, efficiently binds to TRPV1, prevents high fat diet-induced weight gain, and upregulates thermogenic protein expression in WAT. Molecular docking studies indicate that capsaicin exhibits the highest binding efficacy to TRPV1 because it has a hydrogen bond that anchors it to TRPV1. Capsiate, which lacks the hydrogen bond, and therefore, does not anchor to TRPV1. (4) Conclusions: Long-term activation of TRPV1 is imminent for the anti-obesity effect of capsaicin. Efforts to decrease the pungency of capsaicin will help in advancing it to mitigate obesity and metabolic dysfunction in humans.

scholarly journals Synthesis, Anticonvulsant Evaluation and Molecular Docking Studies of Novel Benzo[1,3]dioxol-5-yloxy-N′-(4-substituted benzylidene)acetohydrazide Derivatives

2019 ◽  
Vol 32 (1) ◽  
pp. 199-204
Author(s):  
Shailesh Kumar Singh ◽  
Laxmi Tripathi
Keyword(s):  
Molecular Docking ◽  
Mechanism Of Action ◽  
Anticonvulsant Activity ◽  
Docking Studies ◽  
Probable Mechanism ◽  
Aminobutyric Acid ◽  
Docking Score ◽  
Acid Receptor ◽  
Seizure Models ◽  
Gabaergic Activity

Novel (benzo[1,3]dioxol-5-yloxy)-N′-(4-substituted benzylidene)acetohydrazide derivatives were synthesized and their anticonvulsant activity evaluated by MES and scMET seizure models. Compound 2-(benzo[d][1,3]dioxol-5-yloxy)-N′-benzylideneacetohydrazide (4a) was found to be most potent in MES seizure test and showed no neurotoxicity at the highest administered dose. All the compounds showed high docking score with γ-aminobutyric acid receptor, GABAAR-β3 homopentamer (PDB ID: 4COF). Thus, the probable mechanism of action of benzo[1,3]dioxol-5-yloxy-N′-(4-substituted benzylidene)acetohydrazide derivatives (4a-h) may be augmentation of GABAergic activity.

scholarly journals Structural Basis of Binding and Rationale for the Potent Urease Inhibitory Activity of Biscoumarins

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Muhammad Arif Lodhi ◽  
Sulaiman Shams ◽  
Muhammad Iqbal Choudhary ◽  
Atif Lodhi ◽  
Zaheer Ul-Haq ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Active Sites ◽  
Docking Simulation ◽  
Cysteine Residue ◽  
Structural Basis ◽  
Bacillus Pasteurii ◽  
Nickel Ions ◽  
Jack Bean ◽  
Uv Visible

Urease belongs to a family of highly conserved urea-hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and reactive cysteine residue in the active sites. In the current study we examined a series of biscoumarins1–10for their mechanisms of inhibition with the nickel containing active sites of Jack bean andBacillus pasteuriiureases. All these compounds competitively inhibited Jack bean urease through interaction with the nickel metallocentre, as deduced from Michaelis-Menten kinetics, UV-visible absorbance spectroscopic, and molecular docking simulation studies. Some of the compounds behaved differently in case ofBacillus pasteuriiurease. We conducted the enzyme kinetics, UV-visible spectroscopy, and molecular docking results in terms of the known protein structure of the enzyme. We also evaluated possible molecular interpretations for the site of biscoumarins binding and found that phenyl ring is the major active pharmacophore. The excellent in vitro potency and selectivity profile of the several compounds described combined with their nontoxicity against the human cells and plants suggest that these compounds may represent a viable lead series for the treatment of urease associated problems.

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