scholarly journals An ancient dental signalling centre supports homology of an enamel knot in sharks

2021 ◽  
Author(s):  
Alexandre P Thiery ◽  
Ariane S. I. Standing ◽  
Rory L Cooper ◽  
Gareth J Fraser
Keyword(s):  
Small Molecule ◽  
In Silico ◽  
Tooth Development ◽  
Tooth Size ◽  
Enamel Knot ◽  
Functional Conservation ◽  
Scyliorhinus Canicula ◽  
Upstream Regulator ◽  
Fgf Signalling ◽  
Canonical Wnt

Development of tooth cusps is regulated by the enamel knot signalling centre. Fgf signalling regulates differential proliferation between the enamel knot and adjacent dental epithelia during tooth development, leading to formation of the dental cusp. The presence of an enamel knot in non-mammalian vertebrates is debated given differences in signalling. Here we show the conservation and restriction of fgf10 and fgf3 to the sites of future dental cusps in the shark (Scyliorhinus canicula), whilst also highlighting striking differences between the shark and mouse. We reveal shifts in tooth size, shape and cusp number following small molecule perturbations of canonical Wnt signalling. Resulting tooth phenotypes mirror observed effects in mammals, where canonical Wnt has been implicated as an upstream regulator of enamel knot signalling. In silico modelling of shark dental morphogenesis demonstrates how subtle changes in activatory and inhibitory signals can alter tooth shape, resembling phenotypes observed following experimental Wnt perturbation. Our results support the functional conservation of an enamel knot-like signalling centre throughout vertebrates and suggest that varied tooth types from sharks to mammals follow a similar developmental bauplan. Lineage-specific differences in signalling are not sufficient in refuting homology of this signalling centre, which is likely older than teeth themselves.

In silico identification of novel small molecule umami peptide from ovotransferrin

2021 ◽  
Author(s):  
Wenzhu Zhao ◽  
Jingbo He ◽  
Zhipeng Yu ◽  
Sijia Wu ◽  
Jianrong Li ◽  
...  
Keyword(s):  
Small Molecule ◽  
In Silico ◽  
In Silico Identification

Probing Small-Molecule Binding to Cytochrome P450 2D6 and 2C9: An In Silico Protocol for Generating Toxicity Alerts

ChemMedChem ◽  
2010 ◽  
Vol 5 (12) ◽  
pp. 2088-2101 ◽  
Author(s):  
Gianluca Rossato ◽  
Beat Ernst ◽  
Martin Smiesko ◽  
Morena Spreafico ◽  
Angelo Vedani
Keyword(s):  
Cytochrome P450 ◽  
Small Molecule ◽  
In Silico ◽  
Cytochrome P450 2D6 ◽  
P450 2D6

In Silico Discovery of a Small Molecule Suppressing Lung Carcinoma A549 Cells Proliferation and Inducing Autophagy via mTOR Pathway Inhibition

2018 ◽  
Vol 15 (11) ◽  
pp. 5427-5436 ◽  
Author(s):  
Jiyuan Liu ◽  
Li Liu ◽  
Zhen Tian ◽  
Yifan Li ◽  
Changhong Shi ◽  
...  
Keyword(s):  
Small Molecule ◽  
Lung Carcinoma ◽  
In Silico ◽  
A549 Cells ◽  
Mtor Pathway ◽  
Pathway Inhibition

scholarly journals High Throughput in Silico Identification of Novel Phytochemical Inhibitors for the Master Regulator of Inflammation (TNFα)

2021 ◽  
Author(s):  
Pratap Kumar Parida ◽  
Dipak Paul ◽  
Debamitra Chakravorty
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
In Silico ◽  
Small Molecule Inhibitors ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Compound Libraries ◽  
Relative Binding

<p><a>The over expression of Tumor necrosis factor-α (TNFα) has been implicated in a variety of disease and is classified as a therapeutic target for inflammatory diseases (Crohn disease, psoriasis, psoriatic arthritis, rheumatoid arthritis).Commercially available therapeutics are biologics which are associated with several risks and limitations. Small molecule inhibitors and natural compounds (saponins) were identified by researchers as lead molecules against TNFα, however, </a>they were often associated with high IC50 values which can lead to their failure in clinical trials. This warrants research related to identification of better small molecule inhibitors by screening of large compound libraries. Recent developments have demonstrated power of natural compounds as safe therapeutics, hence, in this work, we have identified TNFα phytochemical inhibitors using high throughput <i>in silico </i>screening approaches of 6000 phytochemicals followed by 200 ns molecular dynamics simulations and relative binding free energy calculations. The work yielded potent hits that bind to TNFα at its dimer interface. The mechanism targeted was inhibition of oligomerization of TNFα upon phytochemical binding to restrict its interaction with TNF-R1 receptor. MD simulation analysis resulted in identification of two phytochemicals that showed stable protein-ligand conformations over time. The two compounds were triterpenoids: Momordicilin and Nimbolin A with relative binding energy- calculated by MM/PBSA to be -190.5 kJ/Mol and -188.03 kJ/Mol respectively. Therefore, through this work it is being suggested that these phytochemicals can be used for further <i>in vitro</i> analysis to confirm their inhibitory action against TNFα or can be used as scaffolds to arrive at better drug candidates.</p>

scholarly journals Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

2020 ◽  
Author(s):  
Jamie A. Kelly ◽  
Alexandra N. Olson ◽  
Krishna Neupane ◽  
Sneha Munshi ◽  
Josue San Emeterio ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Small Molecule ◽  
Ribosomal Frameshift ◽  
Short Term ◽  
X Ray ◽  
Functional Conservation ◽  
Lead Compounds ◽  
X Ray Scattering ◽  
The World ◽  
Functional Analyses

Abstract17 years after the SARS-CoV epidemic, the world is facing the COVID-19 pandemic. COVID-19 is caused by a coronavirus named SARS-CoV-2. Given the most optimistic projections estimating that it will take over a year to develop a vaccine, the best short-term strategy may lie in identifying virus-specific targets for small molecule interventions. All coronaviruses utilize a molecular mechanism called −1 PRF to control the relative expression of their proteins. Prior analyses of SARS-CoV revealed that it employs a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of −1 PRF, and that it also harbors a −1 PRF attenuation element. Altering −1 PRF activity negatively impacts virus replication, suggesting that this molecular mechanism may be therapeutically targeted. Here we present a comparative analysis of the original SARS-CoV and SARS-CoV-2 frameshift signals. Structural and functional analyses revealed that both elements promote similar rates of −1 PRF and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablated −1 PRF activity. The upstream attenuator hairpin activity has also been functionally retained. Small-angle x-ray scattering indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 had the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit −1 PRF was similarly effective against −1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may provide promising lead compounds to counter the current pandemic.

Abstract 469: Targeting Beta Adrenergic Receptor Resensitization Aids in Preservation of Receptor Function

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Elizabeth E Martellli ◽  
Yu Sun ◽  
John George ◽  
Maradumane L Mohan ◽  
Randall Starling ◽  
...  
Keyword(s):  
Heart Failure ◽  
Small Molecule ◽  
In Silico ◽  
Adrenergic Receptor ◽  
Human Heart ◽  
Receptor Function ◽  
Human Heart Failure ◽  
Pp2a Activity ◽  
Pi3k Activity ◽  
Underlying Mechanisms

Beta adrenergic receptor (βAR) down-regulation and desensitization are hallmarks of heart failure. Traditionally, it has been considered that increased desensitization mechanisms underlie βAR dysfunction in heart failure but it is not known whether resensitization of βARs is altered and is an integral contributor to heart failure. We have previously shown that resensitization is regulated by inhibition of PP2A by I2PP2A via PI3Kγ (Vasudevan et. al., 2011), the underlying mechanisms of I2PP2A binding to PP2A are not well understood. We used PyMOL software to find the binding interaction between PP2A and I2PP2A. Based on in silico predictions, we generated a mutant PP2A that when expressed would compete out I2PP2A and inhibit I2PP2A from binding to endogenous PP2A. Expression of PP2A mutant in β2AR expressing cells showed preservation of β2AR function following stimulation as measured by reduced β2AR phosphorylation, increased cAMP generation and increased phosphatase function. We also generated a small molecule from our in silico predictions that could target the interface of I2PP2A and PP2A binding to find that disruption of the PP2A/I2PP2A interaction underlies receptor function. We will use this small molecule to look at preservation of βAR function and amelioration of cardiac function. To test whether resensitization is altered in heart failure we used plasma membrane and endosomal fractions from non-failing and paired pre- and post-LVAD samples to show PI3K activity, PP2A activity, β2AR phosphorylation and adenylyl cyclase activity as a measure of recovery in βAR function. Our studies showed that endosomal fractions from human heart failure samples had elevated PI3K activity associated with reduced PP2A activity supporting the idea that βAR resensitization is inhibited in human heart failure samples. Since human heart failure samples have inhibited resensitization we tested the underlying mechanisms regulating βAR resensitization. Thus ongoing studies suggest that targeting the resensitization of βAR could provide beneficial cardiac remodeling in conditions of chronic mechanical overload and will be further discussed.

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