scholarly journals An Efficient Synthesis Towards the Core of Crinipellin and Alliacol-B Along With Their Docking Studies

2020 ◽  
Author(s):  
Raghaba Sahu ◽  
Ranjan Kumar Mohapatra ◽  
Saud I. Al-Resayes ◽  
Debadutta Das ◽  
Pankaj K. Parhi ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Efflux Pump ◽  
Therapeutic Potential ◽  
Docking Study ◽  
Docking Studies ◽  
Alder Reaction ◽  
Multidrug Efflux Pump ◽  
Prostaglandin Synthase ◽  
Human Estrogen Receptor ◽  
Tetracyclic Core

In this present work, we are reporting a novel route for the synthesis of the tetracyclic ring systems, which is a common core of crinipellin via oxidative dearomatization, cycloaddition and oxa- di-pi-methane rearrangement. We considered to exploring a route to tetracyclic core (1e) of Crinipellin and tricyclic core (1g) of Allicaol B through intermolecular diels alder reaction and photochemically 1,2 acyl shift. Moreover, docking study of compound 13 and 16has been investigated against AcrB multidrug efflux pump of Escherichia coli (PDB ID: 1T9U), main protease of SARS COV-2 (PDB ID: 6W63), DNA gyrase of Streptococcus pneumonia (PDB ID: 4Z2C), human estrogen receptor alpha (PDB ID: 3ERT), human lanosterol 14-alpha-demethylase (CYP51)(PDB ID: 3JUS) and cyclooxygenase-2 (Prostaglandin Synthase-2) (PDB ID: 1CX2). The obtained results herein are important for the exploitation of the therapeutic potential of these derivatives as antimicrobial, antiviral, anticancer, antifungal or anti-inflammatory agents.

IN SILICO MOLECULAR DOCKING STUDY OF CONSTITUENTS FROM APPLE AND PASSION FRUIT FOR THE TREATMENT OF INFLAMMATORY BOWEL DISORDER TARGETING INFLAMMATORY PATHWAY

INDIAN DRUGS ◽  
2021 ◽  
Vol 58 (01) ◽  
pp. 47-63
Author(s):  
V. S. Arya ◽  
◽  
S. K. Kanthlal
Keyword(s):  
Molecular Docking ◽  
Therapeutic Potential ◽  
Docking Study ◽  
Docking Studies ◽  
Passion Fruit ◽  
Molecular Docking Study ◽  
Inflammatory Bowel Disorder ◽  
Inflammatory Conditions ◽  
Inflammatory Bowel ◽  
Bowel Disorder

Inflammatory bowel disorder is a group of inflammatory conditions of the colon and small intestine with greater prevalence among the Indian population. Our focus is to explore and compare the therapeutic potential of phytoconstituents from apple and passion fruit by assessing the affinity with the target sites such as JAK/STAT, MPO and iNOS by molecular docking studies. ADMET prediction and drug-likeness were also conducted to screen out the best-fit ligands, whic are expected to be biologically effective. Few selected constituents displayed considerable binding affinity with the selected targets in our docking study. Interestingly, ligands of phenolic nature displayed the highest inhibitory activity by forming strong hydrogen bonding and van der Waals force with the amino acid residues of the target protein. Comparative study proves that constituents of apple showed better effect than passion fruit. It helps to give the existing information to identify precise targets for the selected drugs. However, the results are preliminary and experimental evaluation needs to be done for obtaining the confirmatory results.

scholarly journals Biological Activities of Withanolides from Datura innoxia

2021 ◽  
pp. 43-54
Author(s):  
Ruby George ◽  
Priti Mathur
Keyword(s):  
Efflux Pump ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Antibacterial Properties ◽  
Docking Studies ◽  
Datura Innoxia ◽  
Ligand Interaction ◽  
E Coli ◽  
Antibacterial Assay ◽  
In Silico Studies

Aims: This study aimed to explore the therapeutic potential of Datura innoxia through the chemoinformatic and antibacterial evaluation of withanolides extracted from it. Study Design: The pharmacokinetic and pharmacodynamic properties and drug-likeness of the withanolides—withametelinol A, withametelinol B, witharifeen, withametelin, dinoxin B, and daturalicin—of D. innoxia were analyzed using the SwissADME program. Schrodinger software was used to target and evaluate their antibacterial potentialities through docking studies. The penicillin-binding protein, DNA gyrase, efflux pump protein, and quorum sensing regulators of S. aureus and E. coli were selected as target proteins for assessing protein–ligand interactions. All observations were comparatively analyzed with the properties of withanolide A and withaferin A, the best-known withanolides. Most active dinoxin B withanolide (12500–100000 μg/ml) extracted from leaves of Datura innoxia; was subjected to antibacterial assay against methicillin-resistant S. aureus (MRSA) and multi-drug resistant(MDR) E. coli isolated from the urine samples of urinary tract infected patients. Results: In-silico studies revealed the therapeutical properties of various withanolides present in D. innoxia. In particular, the drug-likeness and antibacterial properties of withametelin and dinoxin B were significantly and remarkably high due to their binding affinity toward cell membrane proteins. Docking studies have shown that the efflux pump protein of E. coli and penicillin-binding proteins of S. aureus to be the ligand -interaction targets. A significant antibacterial assay revealed that the MRSA isolates were susceptible to dinoxin B, with a zone of inhibition of 21±0.5 mm to 24±0.5 mm, and the bacteria were susceptible at a concentration rate of ≤ 12.5 mg/ml. Conclusion: It is crucial to bring awareness of the therapeutical importance of D. innoxia and to preserve this vital plant from being largely destroyed. As computational studies promote the effective selection of drug molecules, this research also helps to select the best compound for further clinical analysis.

scholarly journals Therapeutic Potential of Dietary Polyphenols

2021 ◽  
Author(s):  
Amy L. Stockert ◽  
Seth Hall
Keyword(s):  
Transcription Factors ◽  
Oxidative Damage ◽  
Efflux Pump ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Epigenetic Modifications ◽  
Inflammatory Factors ◽  
Multidrug Efflux Pump ◽  
Disease States ◽  
Regulatory Enzymes

The chapter summarizes available research on polyphenols and the potential for polyphenol based therapeutics. Polyphenols have the potential to be used in a multi-target fashion therapeutically. The majority of the polyphenol benefits appear to share positive effects across multiple disease states including inflammatory diseases, diseases of metabolic dysregulation and cancer. The reviewed literature includes human, animal and cell culture based studies. Selected mechanisms within each disease state are highlighted including interleukin inflammatory markers, NF-κB, acetyl-CoA concentration regulation of metabolism, and p-glycoprotein multidrug efflux pump associated with cancer treatment failures. Reviewed studies discuss polyphenols inhibiting transcription factors that control expression on inflammatory factors as well as activating other transcription factors that increase expression of enzymes protective of oxidative damage. Levels of metabolic regulatory enzymes are also affected positively by polyphenol addition through epigenetic modifications. Epigenetic modifications affecting cancer development and progression appear positively affected by polyphenol treatment. Additionally, oxidative damage protection of normal cells can be achieved by polyphenol treatment thus limiting chemotherapeutic damage. Upon review of the available literature, a strong case for the potential use of polyphenols in therapeutic situations stands out. Potential risks included are that the purity and specific concentrations required to achieve therapeutic benefits without potential side effects need to be examined prior to the adoption of therapeutics.

Hetero-Tricyclic Lead Scaffold as Novel PDE5A Inhibitor for Antihypertensive Activity: In Silico Docking Studies

2019 ◽  
Vol 15 (4) ◽  
pp. 318-333
Author(s):  
Dipak P. Mali ◽  
Neela M. Bhatia
Keyword(s):  
In Silico ◽  
Docking Study ◽  
Docking Studies ◽  
Antihypertensive Activity ◽  
In Silico Docking ◽  
Π Stacking ◽  
Π Stacking Interaction ◽  
Nitrogen Heteroatom ◽  
Inhibitory Potential ◽  
Vlife Mds

Objective:To screen the phytochemicals for phosphodiesterase 5A (PDE5A) inhibitory potential and identify lead scaffolds of antihypertensive phytochemicals using in silico docking studies.Methods:In this perspective, reported 269 antihypertensive phytochemicals were selected. Sildenafil, a PDE5A inhibitor was used as the standard. In silico docking study was carried out to screen and identify the inhibiting potential of the selected phytochemicals against PDE5A enzyme using vLife MDS 4.4 software.Results:Based on docking score, π-stacking, H-bond and ionic interactions, 237 out of 269 molecules were selected which have shown one or more interactions. Protein residue Gln817A was involved in H-boding whereas Val782A, Phe820A and Leu804A were involved in π-stacking interaction with ligand. The selected 237 phytochemicals were structurally diverse, therefore 82 out of 237 molecules with one or more tricycles were filtered out for further analysis. Amongst tricyclic molecules, 14 molecules containing nitrogen heteroatom were selected for lead scaffold identification which finally resulted in three different basic chemical backbones like pyridoindole, tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline as lead scaffolds.Conclusion:In silico docking studies revealed that nitrogen-containing tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline tricyclic lead scaffolds have emerged as novel PDE5A inhibitors for antihypertensive activity. The identified lead scaffolds may provide antihypertensive lead molecules after its optimization.

Towards further Understanding the Structural Requirements of Combretastatin- like Chalcones as Inhibitors of Microtubule Polymerization

2020 ◽  
Vol 16 (2) ◽  
pp. 155-166
Author(s):  
Naveen Dhingra ◽  
Anand Kar ◽  
Rajesh Sharma
Keyword(s):  
Three Dimensional ◽  
3D Qsar ◽  
Docking Study ◽  
Structure Activity Relationship ◽  
Docking Studies ◽  
Activity Relationship ◽  
Structural Requirement ◽  
Ligand Interaction ◽  
Microtubule Polymerization ◽  
Structure Activity

Background: Microtubules are dynamic filamentous cytoskeletal structures which play several key roles in cell proliferation and trafficking. They are supposed to contribute in the development of important therapeutic targeting tumor cells. Chalcones are important group of natural compounds abundantly found in fruits & vegetables that are known to possess anticancer activity. We have used QSAR and docking studies to understand the structural requirement of chalcones for understanding the mechanism of microtubule polymerization inhibition. Methods: Three dimensional (3D) QSAR (CoMFA and CoMSIA), pharmacophore mapping and molecular docking studies were performed for the generation of structure activity relationship of combretastatin-like chalcones through statistical models and contour maps. Results: Structure activity relationship revealed that substitution of electrostatic, steric and donor groups may enhance the biological activity of compounds as inhibitors of microtubule polymerization. From the docking study, it was clear that compounds bind at the active site of tubulin protein. Conclusion: The given strategies of modelling could be an encouraging way for designing more potent compounds as well as for the elucidation of protein-ligand interaction.

scholarly journals Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

2021 ◽  
Vol 22 (4) ◽  
pp. 2062
Author(s):  
Aneta Kaczor ◽  
Karolina Witek ◽  
Sabina Podlewska ◽  
Veronique Sinou ◽  
Joanna Czekajewska ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Efflux Pump ◽  
Gram Negative Bacteria ◽  
Potential Mechanism ◽  
Multidrug Efflux ◽  
Aromatic Rings ◽  
Allosteric Site ◽  
Multidrug Efflux Pump ◽  
Dual Action

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7–23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14–16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7–23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal “dual action” for β-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro.

scholarly journals Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug

2021 ◽  
Vol 14 (7) ◽  
pp. 685
Author(s):  
Sandra Amanda Kozieł ◽  
Monika Katarzyna Lesiów ◽  
Daria Wojtala ◽  
Edyta Dyguda-Kazimierowicz ◽  
Dariusz Bieńko ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Serum Proteins ◽  
Docking Study ◽  
Minor Groove ◽  
Docking Studies ◽  
Minor Groove Binding ◽  
Binding Modes ◽  
Groove Binding ◽  
Molecular Docking Study ◽  
Threading Intercalation

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues.

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