ProteinsPlus: interactive analysis of protein–ligand binding interfaces

Schöning-Stierand, Katrin; Diedrich, Konrad; Fährrolfes, Rainer; Flachsenberg, Florian; Meyder, Agnes; Nittinger, Eva; Steinegger, Ruben; Rarey, Matthias

doi:10.1093/nar/gkaa235

Cited by 156 publications

(104 citation statements)

References 43 publications

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“…Moreover, the PDB structure 6W61 was validated against the X-ray crystal structure of nsp10-nsp16 by Krafcikova et al (PDB ID:6YZ1) [ 36 ] using PyMOL [ 37 ]. Furthermore, to detect potential binding pocket based on the structure nsp10-nsp16, Protein Plus DoGSiteScorer [ 38 ], binding site detection was used to calculate the druggability score. The druggability score values range between zero and one, whereby the higher the score suggests the pocket is estimated to be more druggable.…”

Section: Methodsmentioning

confidence: 99%

Molecular Simulation-Based Investigation of Highly Potent Natural Products to Abrogate Formation of the nsp10–nsp16 Complex of SARS-CoV-2

et al. 2021

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The SARS-CoV-2 non-structural protein (nsp) nsp10–nsp16 complex is essential for the 2′-O-methylation of viral mRNA, a crucial step for evading the innate immune system, and it is an essential process in SARS-CoV-2 life cycle. Therefore, detecting molecules that can disrupt the nsp10–nsp16 interaction are prospective antiviral drugs. In this study, we screened the North African Natural Products database (NANPDB) for molecules that can interact with the nsp10 interface and disturb the nsp10–nsp16 complex formation. Following rigorous screening and validation steps, in addition to toxic side effects, drug interactions and a risk /benefit assessment, we identified four compounds (genkwanin-6-C-beta-glucopyranoside, paraliane diterpene, 4,5-di-p-trans-coumaroylquinic acid and citrinamide A) that showed the best binding affinity and most favourable interaction with nsp10 interface residues. To understand the conformational stability and dynamic features of nsp10 bound to the four selected compounds, we subjected each complex to 200 ns molecular dynamics simulations. We then calculated the free binding energies of compounds interacting with nsp10 structure using the molecular mechanics-generalised Born surface area (MMGBSA). Of the four compounds, genkwanin-6-C-beta-glucopyranoside demonstrated the most stable complex with nsp10, in addition to a tighter binding affinity of −37.4 ± 1.3 Kcal/mol. This potential to disrupt the nsp10–nsp16 interface interaction and inhibit it now sets the path for functional studies.

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Section: Methodsmentioning

confidence: 99%

Molecular Simulation-Based Investigation of Highly Potent Natural Products to Abrogate Formation of the nsp10–nsp16 Complex of SARS-CoV-2

et al. 2021

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“…The human Iba1 3D structure was retrieved from Protein Data Bank (PDB ID: 2D58) and was used to perform molecular docking with natural products such as Curcumin, Cannabidiol, Ginsenosides, Resveratrol and Sulforane using AutoDock 4.2 (Morris et al, 2009). Further, visualization of drug pockets on Iba1 protein, protein-ligand interaction and analysis of hydrogen bond formation was analyzed by ProteinsPlus server (Schöning-Stierand et al, 2020) and LigPlot2. The DoGSiteScorer analysis of ProteinsPlus server for predicting potential drug binding sites (pockets) showed presence of 5 drug pocket sites on Iba1 which can be used for drug binding.…”

Section: Sulforaphanementioning

confidence: 99%

Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

et al. 2021

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Microglia, a type of innate immune cell of the brain, regulates neurogenesis, immunological surveillance, redox imbalance, cognitive and behavioral changes under normal and pathological conditions like Alzheimer’s, Parkinson’s, Multiple sclerosis and traumatic brain injury. Microglia produces a wide variety of cytokines to maintain homeostasis. It also participates in synaptic pruning and regulation of neurons overproduction by phagocytosis of neural precursor cells. The phenotypes of microglia are regulated by the local microenvironment of neurons and astrocytes via interaction with both soluble and membrane-bound mediators. In case of neuron degeneration as observed in acute or chronic neurodegenerative diseases, microglia gets released from the inhibitory effect of neurons and astrocytes, showing activated phenotype either of its dual function. Microglia shows neuroprotective effect by secreting growths factors to heal neurons and clears cell debris through phagocytosis in case of a moderate stimulus. But the same microglia starts releasing pro-inflammatory cytokines like TNF-α, IFN-γ, reactive oxygen species (ROS), and nitric oxide (NO), increasing neuroinflammation and redox imbalance in the brain under chronic signals. Therefore, pharmacological targeting of microglia would be a promising strategy in the regulation of neuroinflammation, redox imbalance and oxidative stress in neurodegenerative diseases. Some studies present potentials of natural products like curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane to suppress activation of microglia. These natural products have also been proposed as effective therapeutics to regulate the progression of neurodegenerative diseases. The present review article intends to explain the molecular mechanisms and functions of microglia and molecular dynamics of microglia specific genes and proteins like Iba1 and Tmem119 in neurodegeneration. The possible interventions by curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane on microglia specific protein Iba1 suggest possibility of natural products mediated regulation of microglia phenotypes and its functions to control redox imbalance and neuroinflammation in management of Alzheimer’s, Parkinson’s and Multiple Sclerosis for microglia-mediated therapeutics.

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“…The molecular graphics program incorporated in 1-Clik Mcule was used for structural visualization of protein-ligand interactions and to obtain the snapshot of Fig. 4, while the protein-ligand interaction diagram shown in the same figure was obtained by ProteinsPlus (https :// prote ins.plus/) (Rarey et al 2020).…”

Section: Molecular Dockingmentioning

confidence: 99%

Lower COVID-19 mortality in Italian forested areas suggests immunoprotection by Mediterranean plants

Roviello

2020

Environ Chem Lett

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The COVID-19 pandemic has induced dramatic effects on the population of the industrialized north of Italy, whereas it has not heavily affected inhabitants of the southern regions. This might be explained in part by human exposure to high levels of fine particulate matter (PM) in the air of northern Italy, thus exacerbating the mortality. Since trees mitigate air pollution by intercepting PM onto plant surfaces and bolster the human immune system by emitting bioactive volatile organic compounds (VOCs), we hypothesize a protective role of evergreen forested areas in southern Italy. We compared the mortality rate due to COVID-19, the death number, the positivity rate and the forest coverage per capita in various Italian regions. Hectares of forest per capita and prevalence of deciduous versus evergreen forestal species were also estimated. In silico docking studies of potentially protective compounds found in Laurus nobilis L., a typical Mediterranean plant, were performed to search for potential antivirals. We found that the pandemic's severity was generally lower in southern regions, especially those with more than 0.3 hectares of forest per capita. The lowest mortality rates were found in southern Italy, mainly in regions like Molise (0.007%) and Basilicata (0.005%) where the forest per capita ratio is higher than 0.5 Ha/person. Our findings suggest that evergreen Mediterranean forests and shrubland plants could have protected the southern population by emission of immunomodulating VOCs and provision of dietary sources of bioactive compounds. Moreover, in silico studies revealed a potential anti-COVID-19 activity in laurusides, which are unexplored glycosides from bay laurel. Overall, our results highlight the importance of nature conservation and applications to the search for natural antivirals.

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ProteinsPlus: interactive analysis of protein–ligand binding interfaces

Cited by 156 publications

References 43 publications

Molecular Simulation-Based Investigation of Highly Potent Natural Products to Abrogate Formation of the nsp10–nsp16 Complex of SARS-CoV-2

Molecular Simulation-Based Investigation of Highly Potent Natural Products to Abrogate Formation of the nsp10–nsp16 Complex of SARS-CoV-2

Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

Lower COVID-19 mortality in Italian forested areas suggests immunoprotection by Mediterranean plants

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