scholarly journals In silico Nigellidine (N. sativa) bind to viral spike/active-sites of ACE1/2, AT1/2 to prevent COVID-19 induced vaso-tumult/vascular-damage/comorbidity

2021 ◽  
pp. 106856
Author(s):  
Smarajit Maiti ◽  
Amrita Banerjee ◽  
Mehak Kanwar
Keyword(s):  
In Silico ◽  
Active Sites ◽  
Vascular Damage

scholarly journals Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19)

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 460
Author(s):  
Amr El-Demerdash ◽  
Ahmed M. Metwaly ◽  
Afnan Hassan ◽  
Tarek Mohamed Abd El-Aziz ◽  
Eslam B. Elkaeed ◽  
...  
Keyword(s):  
In Silico ◽  
Active Sites ◽  
Specific Treatment ◽  
Aqueous Solubility ◽  
Maximum Tolerated Dose ◽  
Binding Energies ◽  
Log P ◽  
Binding Affinities ◽  
Structural Protein ◽  
Guanidine Alkaloids

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = −8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = −6.49 kcal/mol), and nsp10 (ΔG = −9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = −7.99 kcal/mol), spike glycoproteins (ΔG = −6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = −8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.

scholarly journals Potential Anticancer Lipoxygenase Inhibitors from the Red Sea-Derived Brown Algae Sargassum cinereum: An In-Silico-Supported In-Vitro Study

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 416
Author(s):  
Sami I. Alzarea ◽  
Abeer H. Elmaidomy ◽  
Hani Saber ◽  
Arafa Musa ◽  
Mohammad M. Al-Sanea ◽  
...  
Keyword(s):  
Red Sea ◽  
Antiproliferative Activity ◽  
Inhibitory Activity ◽  
Brown Algae ◽  
In Silico ◽  
Active Sites ◽  
In Vitro Study ◽  
Lipoxygenase Inhibitors ◽  
Phytochemical Investigation

LC-MS-assisted metabolomic profiling of the Red Sea-derived brown algae Sargassum cinereum “Sargassaceae” dereplicated eleven compounds 1–11. Further phytochemical investigation afforded two new aryl cresol 12–13, along with eight known compounds 14–21. Both new metabolites, along with 19, showed moderate in vitro antiproliferative activity against HepG2, MCF-7, and Caco-2. Pharmacophore-based virtual screening suggested both 5-LOX and 15-LOX as the most probable target linked to their observed antiproliferative activity. The in vitro enzyme assays revealed 12 and 13 were able to inhibit 5-LOX more preferentially than 15-LOX, while 19 showed a convergent inhibitory activity toward both enzymes. Further in-depth in silico investigation revealed the molecular interactions inside both enzymes’ active sites and explained the varying inhibitory activity for 12 and 13 toward 5-LOX and 15-LOX.

scholarly journals An In-Silico Approach for Designing a Potential Antagonistic Molecule Targeting β2-adrenoreceptor Having Therapeutic Significance

2020 ◽  
Vol 10 (2) ◽  
pp. 2063-2069
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Active Sites ◽  
De Novo ◽  
Cellular Level ◽  
Ligand Molecule ◽  
Best Fitting ◽  
Β2 Adrenergic Receptor ◽  
External Stimuli ◽  
G Protein Coupled

One of the largest families of membrane proteins, the G protein-coupled receptors (GPCRs) has been a very important target of drug discovery as they are involved in having a regulatory role in a variety of signaling pathways at the cellular level in response to external stimuli. Modern in-silico and crystallographic approaches have further made it easier to peep into their structures. In this study, β2 adrenergic receptor (β2AR) has been targeted, and a new ligand molecule using the de-novo approach has been proposed. Using 1-Amino-3-(2,3-dihydro-1H-indol-4-yloxy)-propan-2-ol, the best fitting binding fragments were established with a significant dissociation constant value of 5-7 nanomolar. The flexibility of specific active sites was also investigated, and it was observed that residues 114 (V), 117 (V), 203 (S), 286 (W), and 289 (F) played a crucial role in accommodating ligand for the best binding. Upon examination of the bioavailability parameters, the ligand var9 exhibited significant inhibitory characteristics having lower toxicity values and high drug likeliness properties. Findings certainly hold significance in terms of targeting GPCRs in getting insight into structure-based drug designing and drug discovery.

scholarly journals Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico

2020 ◽  
Vol 8 (10) ◽  
pp. 1610 ◽  
Author(s):  
Mitsuru Sada ◽  
Takeshi Saraya ◽  
Haruyuki Ishii ◽  
Kaori Okayama ◽  
Yuriko Hayashi ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Molecular Interactions ◽  
In Silico ◽  
Influenza A ◽  
Active Sites ◽  
Active Form ◽  
Antiviral Drug ◽  
Virus Rna ◽  
Influenza A H1n1 ◽  
In Silico Studies

Favipiravir was initially developed as an antiviral drug against influenza and is currently used in clinical trials against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19). This agent is presumably involved in RNA chain termination during influenza virus replication, although the molecular interactions underlying its potential impact on the coronaviruses including SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) remain unclear. We performed in silico studies to elucidate detailed molecular interactions between favipiravir and the SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza virus RNA-dependent RNA polymerases (RdRp). As a result, no interactions between favipiravir ribofuranosyl-5′-triphosphate (F-RTP), the active form of favipiravir, and the active sites of RdRps (PB1 proteins) from influenza A (H1N1)pdm09 virus were found, yet the agent bound to the tunnel of the replication genome of PB1 protein leading to the inhibition of replicated RNA passage. In contrast, F-RTP bound to the active sites of coronavirus RdRp in the presence of the agent and RdRp. Further, the agent bound to the replicated RNA terminus in the presence of agent, magnesium ions, nucleotide triphosphate, and RdRp proteins. These results suggest that favipiravir exhibits distinct mechanisms of action against influenza virus and various coronaviruses.

scholarly journals Synthesis, Characterization, Biological Screening, ADME and Molecular Docking Studies of 2-Phenyl Quinoline-4-Carboxamide Derivatives

2020 ◽  
Vol 32 (5) ◽  
pp. 1151-1157 ◽  
Author(s):  
P. Raghurama Shetty ◽  
G. Shivaraja ◽  
G. Krishnaswamy ◽  
K. Pruthviraj ◽  
Vivek Chandra Mohan ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Molecular Docking ◽  
Anticancer Activity ◽  
In Silico ◽  
Active Sites ◽  
Docking Studies ◽  
Spectrometric Analysis ◽  
Molecular Docking Studies ◽  
In Vitro Investigation

In this work, some 2-phenyl quinoline-4-carboxamide derivatives (5a-j) were synthesized via base catalyzed Pfitzinger reaction of isatin and acetophenone followed by C-N coupling reaction using POCl3 and assessed them for their in vitro antimicrobial and anticancer activity. The structure of newly synthesized compound were established by FT-IR, 1H & 13C NMR and Mass spectrometric analysis. The synthesized carboxamides were subjected to preliminary in vitro antibacterial activity as well as for antifungal activity. Results of antibacterial activity were compared with standard antibacterial (ciprofloxocin) and antifungal (fluconozole). Among the tested compounds, 5d, 5f and 5h exhibited promising activity with zone of inhibition ranging from 10 to 25 mm. Further, the anticancer activity determined using MTT assay against two cancer cell lines. Compounds 5b, 5d, 5f and 5h showed good anticancer activity among all the other derivatives. In order to correlate the in vitro results, in silico ADME and Molecular docking studies were carried out for (5a-j). ADME properties results showed that all the compounds obey rule of Five rule except 5a, 5e and 5g compound. Molecular docking studies of the synthesized compounds showed good binding affinity through hydrogen bond interactions with key residues on active sites as well as neighboring residues within the active site of chosen target proteins viz. antibacterial, antifungal and anticancer. Comparison of both results of in silico as well as in vitro investigation suggests that the synthesized compounds may act as potential antimicrobial as well as anticancer agents.

scholarly journals NUOVI APPROCCI TEORICI E SPERIMENTALI ALLA SCOPERTA DI FARMACI

2012 ◽  
Author(s):  
Martino Bolognesi
Keyword(s):  
Crystal Structure ◽  
Drug Discovery ◽  
In Silico ◽  
Active Sites ◽  
Yellow Fever Virus ◽  
Enzyme Inhibitor ◽  
Therapeutic Interventions ◽  
Research Activity ◽  
In Silico Docking ◽  
Structural And Functional Properties

New theoretic and experimental approaches to drug discovery. Environmental, demographic and ecological reasons suggest that either novel or known viruses will continue to emerge worldwide, posing new threats to the human population. Additionally, therapeutic interventions present different outcomes; for example, vaccination campaigns in the Third World often encounter local distribution problems and reach an insufficient fraction of the population. For many viruses no vaccine is available, such that the toll death is high, particularly in tropical countries and among infants. On the other hand, resistance of bacteria to know antibiotics is increasingly a serious threat, often associated to nosocomial infections. As a result, new ideas and approaches to the discovery or design of new effective drugs are a high priority in all civilized countries, to prevent and be ready to face potential pandemics. In this context, our group at the University of Milano, in collaboration with several European and extra- European labs, has been exploring the structural and functional properties of enzymes involved in the replication of (+)stranded RNA viruses as targets for the design of antiviral drugs. The rationale behind the choice of specific target viral is the idea that these are structurally and functionally sufficiently different from their human counterparts; thus, blocking the virus enzyme with a new drug should not be reflected by adverse reactions in the human host. The discovery approach applied in our laboratory has been based on a series of specific experimental steps: i) the analysis of crystal structure of the free enzymes, through X-ray crystallography; ii) in silico (computational) preliminary screening of selected enzyme regions towards which the drug search is targeted (e.g. mostly the enzyme active sites); iii) biochemical and biophysical tests of enzyme inhibition; iv) crystal structure analyses of enzyme/inhibitor complexes; v) in cell/in vivo testing; vi) inference for drug-lead optimization. This research method proved effective in discovering low molecular weight inhibitors of two key enzymes from Yellow fever virus (and partly for Dengue virus), and for Norovirus. Specifically, we targeted Norovirus studying the long known drug Suramin (used in the therapy of ‘sleeping sickness’), which was selected through the procedure described above through our in silico docking screenings. Our crystallographic and inhibition assays allowed to highlight the inhibitor binding mode and satisfactory functional inhibitory parameters. Subsequently, in the context of an international collaboration, we could test a series of Suramin molecular fragments, in search of new active compounds endowed with suitable pharmacological parameters. The described research activity, which is based on new conceptual and multidisciplinary approaches to drug discovery, has led to the production of several small molecules that will be further developed into antiviral compounds.

Expression of CspE by a Psychrotrophic Bacterium Enterobacter ludwigii PAS1, Isolated from Indian Himalayan Soil and In silico Protein Modelling, Prediction of Conserved Residues and Active Sites

2013 ◽  
Vol 66 (5) ◽  
pp. 507-514 ◽  
Author(s):  
Premalatha Kandasamy ◽  
Nidarshana Chaturvedi ◽  
Brijesh S. Sisodia ◽  
Ajit K. Shasany ◽  
Shachi Gahoi ◽  
...  
Keyword(s):  
In Silico ◽  
Active Sites ◽  
Protein Modelling ◽  
Conserved Residues ◽  
Psychrotrophic Bacterium ◽  
Enterobacter Ludwigii

scholarly journals A Computational Approach towards the Development of Newer Anticancer Agents

2010 ◽  
Vol 7 (1) ◽  
pp. 21-24 ◽  
Author(s):  
Javed I. Sheikh ◽  
H. D. Juneja ◽  
V. N. Ingle
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Anticancer Agents ◽  
In Silico ◽  
Active Sites ◽  
Computational Approach ◽  
The Novel ◽  
Cytochrome P450 Reductase ◽  
P450 Reductase

In silicomolecular docking analyses of the novel 1-(2', 4'-dihydroxy-5'-chlorophenyl)-3-aryl-propane-1, 3-diones were performed in the active sites of enzyme cytochrome P450 reductase to obtain new anticancer agents computationally. 1-(2', 4'-dihydroxy-5'-chlorophenyl)-3-(4"-methoxy-phenyl)-propane-1, 3-dione(3f)was found to have maximum affinity for the active sites of enzyme.

scholarly journals A Multi-Pronged Approach Targeting SARS-CoV-2 Proteins Using Ultra-Large Virtual Screening

2020 ◽  
Author(s):  
Christoph Gorgulla ◽  
Krishna PadmanabhaDas ◽  
Kendra E. Leigh ◽  
Marco Cespugli ◽  
Patrick D. Fischer ◽  
...  
Keyword(s):  
Virtual Screening ◽  
In Silico ◽  
Active Sites ◽  
Large Scale ◽  
Protein Protein Interaction ◽  
The Face ◽  
Computing Platforms ◽  
Screening Platform ◽  
Novel Coronavirus ◽  
Further Development

<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as 2019 novel coronavirus (2019-nCoV), has spread rapidly across the globe, creating an unparalleled global health burden and spurring a deepening economic crisis. As of July 7th, 2020, almost seven months into the outbreak, there are no approved vaccines and few treatments available. Developing drugs that target multiple points in the viral life cycle could serve as a strategy to tackle the current as well as future coronavirus pandemics. Here we leverage the power of our recently developed <i>in silico</i> screening platform, VirtualFlow, to identify inhibitors that target SARS-CoV-2. VirtualFlow is able to efficiently harness the power of computing clusters and cloud-based computing platforms to carry out ultra-large scale virtual screens. In this unprecedented structure-based multi-target virtual screening campaign, we have used VirtualFlow to screen an average of approximately 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets in the cloud. In addition to targeting the active sites of viral enzymes, we also target critical auxiliary sites such as functionally important protein-protein interaction interfaces. This multi-target approach not only increases the likelihood of finding a potent inhibitor, but could also help identify a collection of anti-coronavirus drugs that would retain efficacy in the face of viral mutation. Drugs belonging to different regimen classes could be combined to develop possible combination therapies, and top hits that bind at highly conserved sites would be potential candidates for further development as coronavirus drugs. Here, we present the top 200 <i>in silico</i> hits for each target site. While in-house experimental validation of some of these compounds is currently underway, we want to make this array of potential inhibitor candidates available to researchers worldwide in consideration of the pressing need for fast-tracked drug development.</p>

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