Fenretinide is a synthetic retinoid compound, which induces apoptosis via generating reactive oxygen species (ROS) and modulating PI3K/Akt/mTOR signalling pathway. We hypothesise that fenretinide's ...mechanism of action in triggering apoptosis may involve other targets, beside mTOR signalling pathway and it may augment apoptosis inducing effects of chemotherapeutic drugs in lung cancer. Time-lapse microscopy and Western blotting were used to evaluate apoptosis and apoptotic marker cleaved-Caspase 3 in A549 cells. Relative levels of protein phosphorylation and ROS were quantified by Human Phospho-Kinase Array Kit and CellROX® Green Reagent, respectively. Docking and simulation analyses of proteins and fenretinide interactions were identified and visualised by Discovery Studio Visualizer and AutoDock Vina software. Our results showed that fenretinide induced apoptosis in a dose dependant manner and combinations of fenretinide (5 μg/mL) and gemcitabine (1, 2, 4, 8 and 16 μg/mL) synergistically enhanced apoptosis in A549 cells. Fenretinide caused significant increase of cleaved-Caspase 3, de-phosphorylated p-S473 of Akt and failed to inhibit mTORC1 downstream targets. In silico results revealed that Akt required the lowest energy (−10.2 kcal/mol) to interact with fenretinide in comparison with other proteins. In conclusion, Akt may be exploited as a good target for induction of apoptosis in A549 cells and fenretinide has great potentials to fulfil this task. The mechanism by which fenretinide boosts the apoptosis inducing effects of gemcitabine, which is likely expected to be via inhibiting mTORC2 downstream targets. However, docking investigation revealed that fenretinide lacks specificity as it may also interact with several secondary targets beside Akt.
•Akt may be exploited as a good target for induction of apoptosis in A549 cells and fenretinide has great potentials to fulfil this task.•Fenretinide promotes the apoptosis inducing effect of gemcitabine synergistically, when used in combination.•The mechanism by which fenretinide boosts the apoptosis inducing effects of gemcitabine is likely to be via inhibiting mTORC2 downstream targets.•Docking investigation revealed that fenretinide lacks specificity as it may also interact with several secondary targets beside Akt.
Objective: Design of novel antimicrobial peptides and study through the molecular docking.Methods: The molecular structures were drawn in ChemBiodraw ultra and by the help of ChemBiodraw 3D, all ...structures were energy minimized by theMM2 method and converted to pdbextension file which is readable at the ADT interface. The AutoDock Vina (ADT) 1.5.6 software is used for molecular docking purposes.Results: Eight antimicrobial peptides (AMPs) were designed based on theMP196antimicrobial peptide. Among these KP_03R (FWRWRW-NH2) showed good binding affinity. These peptides also showed the stereochemical influence on affinity toward the3vma protein of E. coli, where AMP with R stereochemistry showed better activity than its opposite stereochemistry. Conclusion: Novel AMPs were designed by modifications on the MP196 a short chain of amino acids antimicrobial peptides. Molecular docking software was used to determine the binding affinity between drug and receptor protein. Among all the designed peptides KP_03R(FWRWRW-NH2) showed the maximum binding affinity against thepenicillin-binding protein of E.coli and also exhibited stereoselective activity.
•Bio fabrication of gold nanoparticles using brown seaweed Spatoglossum asperum.•Excellent antioxidant activity was demonstrated by the gold nanomaterials.•The Sa-AuNPs have shown anti-cancer ...properties against glioblastoma.•Molecular docking performed against glioblastoma-induced genes with biomolecules of S. asperum.•The findings of invitro and docking analysis proved anticancer effect of Sa-AuNPs.
This research aimed to investigate the mechanism of glioblastoma-killing action of brown seaweed Spatoglossum asperum fabricated gold nanoparticles (Sa-AuNPs) as a novel medication. UV spectroscopy revealed the surface plasmon resonance peak at 530 nm for the stability of bio-fabricated Sa-AuNPs. The XRD and SEM analysis affirmed the Sa-AuNPs were crystalline condition and cubic shapes with 20 nm size. The reducing and capping agents of organic compounds present in the Sa-AuNPs were identified by FTIR, NMR and Mass spectroscopic analysis. In addition, Sa-AuNPs showed excellent antioxidant activity through maximum inhibition of DPPH radicals (73.21%) and hydrogen peroxide radicals (68.9%). The biosynthesized Sa-AuNPs showed potent cytotoxic activity against LN-18 Glioblastoma cells (IC50 = 13.38 μg/mL). Furthermore, 11 genes involved in glioma cancer (as protein) and 10 compounds in the S. asperum (as Ligand) were picked for molecular docking. The docking result showed, among the 10 selected compounds, stigmast-5-en-3-ol has an effective binding affinity with 11 genes and effectively targeted EGFR, IDH and PTEN. This study concludes that Sa-AuNPs have potent antioxidant and anticancer activity due to the presence of bioactive molecules involved in the nanoparticle's reduction process. The research provides strong support for the prospective development of innovative treatments for glioblastoma.
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Proizvodnja vina često se nosi s problemima koje uzrokuju različite vrste plijesni. Mnoge od njih djeluju štetno jer uzrokuju različite bolesti ili izlučuju toksične i potencijalno zdravstveno opasne ...spojeve te smanjuju ukupni prinos i kvalitetu vina. Najznačajnije među njima su plijesni Aspergillus spp., Penicillium spp. i Botrytis cinerea. Međutim, Botrytis cinerea može doprinijeti i značajnom poboljšanju organoleptičkih svojstava vina i omogućiti proizvodnju cijenjenih predikatnih vina. U ovom radu, na osnovu postojećih literaturnih izvora i spoznaja, opisano je pozitivno i negativno djelovanje prisustva plijesni na konačne karakteristike vina.
Rational drug design using in‐silico tools have helped improve the time and possibilities of the development of safer drugs in recent times. This study was designed to develop safer DNA topoisomerase ...1B inhibitors from two parent compounds isolated.
The adsorption, distribution, excretion and toxicity (ADMET) properties of selected isoquinoline compounds were predicted using swiss ADME online tool. Analogues of these compounds were also created using ChemDraw professional Suite 16.0 by adding and removing functional groups based on the pharmacophoric structure of topotecan. 3D in‐silico docking was carried out between the designed compounds and the DNA topoisomerase 1B using AutoDock Vina software. Search space for ligand binding was defined and the program returned the binding affinities between the designed compounds and DNA topoisomerase 1B.
Five analogues were designed for each compound. Out of the analogues designed, parent compound 1‐analogue 3 proved likely to be effective and safe in cancer treatment by having a binding affinity of −9.9 kcal/mol for DNA topoisomerase 1B and good ADMET prediction. The other compound (parent‐2) analogues had very high binding affinities for DNA topoisomerase 1B but they generally had ADMET problems. They were either predicted to be P‐glycoprotein substrates or blood‐brain barrier permeants.
Rational drug design for anticancer agents from selected isoquinolines in Annona muricata predicted study compounds to be safe and effective in inhibiting DNA topoisomerase 1B.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Docking of small molecule compounds into the binding site of a receptor and estimating the binding affinity of the complex is an important part of the structure-based drug design process. For a ...thorough understanding of the structural principles that determine the strength of a protein/ligand complex both, an accurate and fast docking protocol and the ability to visualize binding geometries and interactions are mandatory. Here we present an interface between the popular molecular graphics system PyMOL and the molecular docking suites Autodock and Vina and demonstrate how the combination of docking and visualization can aid structure-based drug design efforts.
This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this ...tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (Mpro) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the Mpro active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV Mpro and the highly homologous SARS-CoV-2 Mpro. The supporting information provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv https://doi.org/10.1101/2020.08.03.234872 describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 Mpro.
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•Tutorial for the structure-based design of a preliminary drug candidate against COVID-19.•Use of free software and publicly available X-ray crystallographic structures.•Illustrated step-by-step protocol as well as a video showing the inhibitor design process.•Teaches readers how to design their own drug candidates.
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