Bax and Bcl-xL exert their regulation on different sites of the ceramide channel

2012 ◽  
Vol 445 (1) ◽  
pp. 81-91 ◽  
Author(s):  
Meenu N. Perera ◽  
Shang H. Lin ◽  
Yuri K. Peterson ◽  
Alicja Bielawska ◽  
Zdzislaw M. Szulc ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Structural Features ◽  
Amide Group ◽  
Binding Modes ◽  
Docking Simulations ◽  
Functional Studies ◽  
Hydrophobic Groove ◽  
Potential Binding ◽  
Ceramide Channels ◽  
Long Chain

The present study demonstrates the important structural features of ceramide required for proper regulation, binding and identification by both pro-apoptotic and anti-apoptotic Bcl-2 family proteins. The C-4=C-5 trans-double bond has little influence on the ability of Bax and Bcl-xL to identify and bind to these channels. The stereochemistry of the headgroup and access to the amide group of ceramide is indispensible for Bax binding, indicating that Bax may interact with the polar portion of the ceramide channel facing the bulk phase. In contrast, Bcl-xL binding to ceramide channels is tolerant of stereochemical changes in the headgroup. The present study also revealed that Bcl-xL has an optimal interaction with long-chain ceramides that are elevated early in apoptosis, whereas short-chain ceramides are not well regulated. Inhibitors specific for the hydrophobic groove of Bcl-xL, including 2-methoxyantimycin A3, ABT-737 and ABT-263 provide insights into the region of Bcl-xL involved in binding to ceramide channels. Molecular docking simulations of the lowest-energy binding poses of ceramides and Bcl-xL inhibitors to Bcl-xL were consistent with the results of our functional studies and propose potential binding modes.

scholarly journals Synthesis, Spectral Characterization and Molecular Docking Studies of Novel Benzidin-bis-tetrahydroacridine Analogues

2020 ◽  
Vol 71 (5) ◽  
pp. 163-181
Author(s):  
Madalina Marina Hrubaru ◽  
Carmellina Daniela Badiceanu ◽  
Anthony Chinonso Ekennia ◽  
Sunday N. Okafor ◽  
Cristian Enache ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Sites ◽  
Docking Studies ◽  
Binding Affinities ◽  
Binding Modes ◽  
Docking Simulations ◽  
Ft Ir ◽  
Dynamics Simulations ◽  
And Behavior ◽  
Human Butyrylcholinesterase

Alzheimer�s is a progresive neurodegenerative disease that interferes with human cognitive ability, memory and behavior. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes are major therapeutic routes for the treatment of Alzheimer disease. In the study, nevel bis-polymethylenquinoline-bis-carboxamides (3a-f) and bis-polymethylenquinoline-bis-carboxylic acids (5a-b) having as precursor benzidine, were obtained in good yields by Pfitzinger condensation reactions of bis-isatines with corresponding cyclanones. The compounds were characterized by elemental analysis, FT-IR, NMR and mass spectrometry. Furthermore, the compounds were subjected to molecular docking dynamics simulations to ascertain their potentials as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Molecular docking simulations showed varied binding activities towards the two binding sites of acetylcholinesterase: 4EY7 and 1OCD, and human butyrylcholinesterase: 1P0I. Compounds 3e and 5b demostrated strong binding affinities with 1P0I, 1OCD and 4EY7 biotargets similar to the binding modes of donepezil and tacrine (co-crystallized inhibitors of acetylcholinesterase) and butyrate (co-crystallized inhibitors of butyrylcholinesterase).

scholarly journals Prostaglandins Isolated from the Octocoral Plexaura homomalla: In Silico and In Vitro Studies Against Different Enzymes of Cancer

Marine Drugs ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 141 ◽  
Author(s):  
Diana Ximena Hurtado ◽  
Fabio A. Castellanos ◽  
Ericsson Coy-Barrera ◽  
Edisson Tello
Keyword(s):  
Molecular Docking ◽  
Enzymatic Activity ◽  
Cell Lines ◽  
Src Kinase ◽  
Binding Modes ◽  
Topoisomerase Iiα ◽  
Docking Simulations ◽  
Prostaglandin A2 ◽  
P38α Kinase

Prostaglandin A2-AcMe (1) and Prostaglandin A2 (2) were isolated from the octocoral Plexaura homomalla and three semisynthetic derivatives (3–5) were then obtained using a reduction protocol. All compounds were identified through one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) experiments. Additionally, evaluation of in vitro cytotoxic activity against the breast (MDA-MB-213) and lung (A549) cancer cell lines, in combination with enzymatic activity and molecular docking studies with the enzymes p38α-kinase, Src-kinase, and topoisomerase IIα, were carried out for compounds 1–5 in order to explore their potential as inhibitors of cancer-related molecular targets. Results showed that prostaglandin A2 (2) was the most potent compound with an IC50 of 16.46 and 25.20 μg/mL against MDA-MB-213 and A549 cell lines, respectively. In addition, this compound also inhibited p38α-kinase in 49% and Src-kinase in 59% at 2.5 μM, whereas topoisomerase IIα was inhibited in 64% at 10 μM. Enzymatic activity was found to be consistent with molecular docking simulations, since compound 2 also showed the lowest docking scores against the topoisomerase IIα and Src-kinase (−8.7 and −8.9 kcal/mol, respectively). Thus, molecular docking led to establish some insights into the predicted binding modes. Results suggest that prostaglandin 2 can be considered as a potential lead for development inhibitors against some enzymes present in cancer processes.

scholarly journals QSAR and Molecular docking studies of 4-anilinoquinoline-triazine hybrids as pf-DHFR inhibitors

2019 ◽  
Vol 8 (2) ◽  
pp. 84
Author(s):  
Hanine Hadni ◽  
Mohamed Mazigh ◽  
Menana El Hallaoui
Keyword(s):  
Molecular Docking ◽  
External Validation ◽  
Docking Study ◽  
Quantitative Structure Activity Relationship ◽  
Structural Features ◽  
Basis Set ◽  
Binding Modes ◽  
Quantum Chemical Descriptors ◽  
Molecular Docking Study ◽  
Mutant Type

<p>A quantitative structure-activity relationship (QSAR) investigation was performed towards 41 hybrids of 4-anilinoquinoline-triazines as potential antimalarial agents. The study was carried out using descendant multiple linear regression analyses (MLR), and artificial neural networks (ANN). Quantum chemical descriptors were calculated using DFT-B3LYP method, with the basis set 6-31G. The values obtained for the correlation coefficient of 0.87 and 0.92 by MLR and ANN, respectively, show a good predictive quality of the established model. In addition, the predicted model has been confirmed by several validation methods such as leave-one-out (LOO) cross-validation, Y-randomization, and external validation. The observed activity and the structural features of the studied molecules were further highlighted by molecular docking study on both wild and quadruple mutant type of <em>pf-DHFR</em> protein. Furthermore, the present work deals to study the binding modes and the key protein-ligand interactions. This methodology will be used to design new antimalarial drugs.</p>

scholarly journals QSAR and Molecular docking studies of 4-anilinoquinoline-triazine hybrids as pf-DHFR inhibitors

2019 ◽  
Vol 8 (2) ◽  
pp. 84-93 ◽  
Author(s):  
Hanine Hadni ◽  
Mohamed Mazigh ◽  
Menana El Hallaoui
Keyword(s):  
Molecular Docking ◽  
External Validation ◽  
Docking Study ◽  
Quantitative Structure Activity Relationship ◽  
Structural Features ◽  
Basis Set ◽  
Binding Modes ◽  
Quantum Chemical Descriptors ◽  
Molecular Docking Study ◽  
Mutant Type

A quantitative structure-activity relationship (QSAR) investigation was performed towards 41 hybrids of 4-anilinoquinoline-triazines as potential antimalarial agents. The study was carried out using descendant multiple linear regression analyses (MLR), and artificial neural networks (ANN). Quantum chemical descriptors were calculated using DFT-B3LYP method, with the basis set 6-31G. The values obtained for the correlation coefficient of 0.87 and 0.92 by MLR and ANN, respectively, show a good predictive quality of the established model. In addition, the predicted model has been confirmed by several validation methods such as leave-one-out (LOO) cross-validation, Y-randomization, and external validation. The observed activity and the structural features of the studied molecules were further highlighted by molecular docking study on both wild and quadruple mutant type of pf-DHFR protein. Furthermore, the present work deals to study the binding modes and the key protein-ligand interactions. This methodology will be used to design new antimalarial drugs.

Homology Modeling of Mus Musculus CDK5 and Molecular Docking Studies with Flavonoids

2017 ◽  
Vol 9 (6) ◽  
Author(s):  
Sowmya Suri ◽  
Rumana Waseem ◽  
Seshagiri Bandi ◽  
Sania Shaik
Keyword(s):  
Molecular Docking ◽  
3D Model ◽  
Structural Features ◽  
Docking Studies ◽  
Amino Acid Residues ◽  
Cyclin Dependent Kinase ◽  
Ligand Complex ◽  
Ligand Interaction ◽  
Molecular Docking Studies ◽  
Cyclin Dependent Kinase 5

A 3D model of Cyclin-dependent kinase 5 (CDK5) (Accession Number: Q543f6) is generated based on crystal structure of P. falciparum PFPK5-indirubin-5-sulphonate ligand complex (PDB ID: 1V0O) at 2.30 Å resolution was used as template. Protein-ligand interaction studies were performed with flavonoids to explore structural features and binding mechanism of flavonoids as CDK5 (Cyclin-dependent kinase 5) inhibitors. The modelled structure was selected on the basis of least modeler objective function. The model was validated by PROCHECK. The predicted 3D model is reliable with 93.0% of amino acid residues in core region of the Ramachandran plot. Molecular docking studies with flavonoids viz., Diosmetin, Eriodictyol, Fortuneletin, Apigenin, Ayanin, Baicalein, Chrysoeriol and Chrysosplenol-D with modelled protein indicate that Diosmetin is the best inhibitor containing docking score of -8.23 kcal/mol. Cys83, Lys89, Asp84. The compound Diosmetin shows interactions with Cys83, Lys89, and Asp84.

Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure

2018 ◽  
Vol 24 (17) ◽  
pp. 1899-1904
Author(s):  
Daniel Fabio Kawano ◽  
Marcelo Rodrigues de Carvalho ◽  
Mauricio Ferreira Marcondes Machado ◽  
Adriana Karaoglanovic Carmona ◽  
Gilberto Ubida Leite Braga ◽  
...  
Keyword(s):  
Heart Failure ◽  
Secondary Metabolites ◽  
Structural Similarity ◽  
Structural Features ◽  
Major Constituent ◽  
Binding Modes ◽  
Starting Point ◽  
In Silico Studies ◽  
Nep Inhibition

Background: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent. Methods: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies. Results: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). Conclusions: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aβ levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

In Silico Approach to Inhibition of Tyrosinase by Ascorbic Acid Using Molecular Docking Simulations

2014 ◽  
Vol 14 (12) ◽  
pp. 1469-1472 ◽  
Author(s):  
F. Senol ◽  
M. Khan ◽  
Gurdal Orhan ◽  
Erdem Gurkas ◽  
Ilkay Orhan ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Molecular Docking ◽  
In Silico ◽  
Docking Simulations

A New Series Of 1,3-Dimethylxanthine Based Adenosine A2a Receptor Antagonists As A Non-Dopaminergic Treatment Of Parkinson’s Disease

2020 ◽  
Vol 17 ◽  
Author(s):  
Suman Rohilla ◽  
Ranju Bansal ◽  
Puneet Chauhan ◽  
Sonja Kachler ◽  
Karl-Norbert Klotz
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Docking Studies ◽  
Binding Modes ◽  
Molecular Docking Studies ◽  
In Silico Docking ◽  
Adenosine A2a Receptor Antagonists ◽  
The Impact

Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties. Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly longlasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

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