scholarly journals Natural phytochemicals, Phenformin, and Docosahexaenoic acid (DHA) as a Novel Inhibitors of IL-6 and ACE2 receptors, a Therapeutic Strategy for targeting COVID-19 Cell Entry and Cytokine Storm. An insilico Approach

2021 ◽  
Author(s):  
Amr kamel khalil Ahmed ◽  
Mahmoud Elkazzaz
Keyword(s):  
Docosahexaenoic Acid ◽  
Binding Affinity ◽  
Active Sites ◽  
Epigallocatechin Gallate ◽  
Cell Entry ◽  
Binding Affinities ◽  
Cytokine Storm ◽  
High Binding ◽  
Life Threatening ◽  
High Binding Affinity

Abstract Cytokine storm syndrome (CSS) is a life-threatening consequence of inflammatory immunological illnesses; it can also occur with COVID-19 infection. CSS is characterized by a disruption in cytokine synthesis, including regulatory, pro-inflammatory and anti-inflammatory cytokines, resulting in pathologic stimulation of innate in addition to adaptive (Th17 and Th1 mediated) response. In the pathophysiology of CSS, interleukin-6 could play a key role. The significant role of IL-6 in COVID-19 pathogenesis was established in a wide variety of researches, which reported that the plasma concentration of IL-6 was raised in COVID-19 patients with severe symptoms. COVID-19 spike protein binding to angiotensin-converting enzyme 2 (ACE2), the virus's cellular receptor, causes a cascade of molecular processes that could result in hyperinflammation which may lead to cytokine storm. Therefore, the development of new natural therapies and repurposing some drugs such as Phenformin and Docosahexaenoic acid that could compete with COVID-19 for ACE2 binding or inhibit IL-6 activity may possibly help COVID-19 patients avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS-CoV-2 RBD attachment to ACE2. Herein we made a docking based screening for some natural phytochemicals and drugs that could be repurposed according to our findings to counter COVID-19 cell entry and inhibit the hyper activation of IL-6. Our results revealed that a five phytochemicals including Epigallocatechin gallate (EGCG), bromelain, luteolin, vitexin and isovitexin) showed a high binding affinities with best interactions with the active sites of IL-6. The binding affinities of these phytochemicals including, EGCG, bromelain, luteolin, vitexin and isovitexin with IL-6 were (-7.7, -6.7, -7.4, -7.2 and − 7.3 ), respectively. In addition to, phenformin showed a high binding affinity with best interactions with the active sites of IL-6 and ACE2. The binding affinity of phenformin with IL-6 was (-7.4) and with ACE 2 ( -7.2). Docosahexaenoic acid (DHA) had a moderate binding affinity and moderate interactions with the active sites of IL-6 and had a high binding affinity with best interactions with ACE2 active sites. The binding affinity of Docosahexaenoic acid(DHA) with IL-6 was (-5.3) and with AC2 (-6.3).ConclusionProposing possible IL-6 inhibitors with less adverse effects has been suggested as a way to aid COVID-19 patients who are suffering from severe cytokine storms. This study has been designed to elucidate the potential of potent antiviral phytocompounds as well as phenformin and Docosahexaenoic acid (DHA) as a potent ACE2 and IL-6 inhibitors. The compounds interact with different active sites of IL6 and ACE2 which are involved in direct or indirect contacts with the ACE2 and IL-6 receptors which might act as potential blockers of functional ACE2 and IL-6 receptor complex. It worth mentioning that phenformin which showed high binding affinity with both ACE2 and IL-6 is currently under investigation for treating COVID-19 ClinicalTrials.gov Identifier: NCT05003492

scholarly journals Natural phytochemicals, Phenformin, and Docosahexaenoic acid (DHA) as a Novel Inhibitors of IL-6 and ACE2 receptors, a Therapeutic Strategy for targeting COVID-19 Cell Entry and Cytokine Storm. An insilico Approach

2021 ◽  
Author(s):  
Amr Kamel Khalil Ahmed ◽  
Mahmoud Elkazzaz
Keyword(s):  
Docosahexaenoic Acid ◽  
Binding Affinity ◽  
Active Sites ◽  
Epigallocatechin Gallate ◽  
Cell Entry ◽  
Binding Affinities ◽  
Cytokine Storm ◽  
High Binding ◽  
Life Threatening ◽  
High Binding Affinity

Cytokine storm syndrome (CSS) is a life-threatening consequence of inflammatory immunological illnesses; it can also occur with COVID-19 infection . CSS is characterized by a disruption in cytokine synthesis, including regulatory , pro-inflammatory andanti-inflammatory cytokines, resulting in pathologic stimulation of innate in addition to adaptive (Th17and Th1mediated) response. In the pathophysiology of CSS, interleukin-6 could play a key role. The significant role of IL-6 in COVID-19pathogenesis was established in a wide variety of researches , which reported that the plasma concentration of IL-6was raised in COVID-19 patients with severe symptoms .COVID-19 spike protein binding to angiotensin-converting enzyme 2 (ACE2), the virus's cellular receptor, causes a cascade of molecular processes that could result in hyperinflammation which may lead to cytokine storm . Therefore, the development of new naturaltherapies and repurposing some drugs such as Phenformin and Docosahexaenoic acidthat could compete with COVID-19 for ACE2 binding or inhibit IL-6 activity may possibly help COVID-19 patients avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS-CoV-2 RBD attachment to ACE2. Herein we made a docking based screening for some natural phytochemicals anddrugs that could be repurposed according to our findings to counter COVID-19 cell entry and inhibitthe hyper activation of IL-6. Our results revealed that a five phytochemicalsincluding Epigallocatechin gallate (EGCG) , bromelain, luteolin , vitexin and isovitexin)showed a high binding affinities with best interactions with the active sites of IL-6 .The binding affinities of these phytochemicalsincluding,EGCG , bromelain, luteolin , vitexin and isovitexinwith IL-6 were (-7.7,-6.7, -7.4, -7.2 and -7.3 ), respectively. In addition to ,phenforminshowed a high binding affinity with best interactions with the active sites of IL-6 and ACE2 . The binding affinity of phenformin with IL-6 was (-7.4) and with ACE 2 ( -7.2).Docosahexaenoic acid (DHA) had a moderate binding affinity and moderate interactions with the active sites of IL-6 and had a high binding affinity with best interactions with ACE2 active sites. The binding affinity of Docosahexaenoic acid(DHA)with IL-6 was (-5.3) and with AC2 (-6.3).

scholarly journals Could docosahexaenoic acid (DHA), found in breast milk and artificial baby milks, protect infants and children from COVID-19 and make them less susceptible to COVID-19-related severe illness, as well as treat adult COVID-19 patients in combination with retinoic acid? A plan for observation and intervention

2021 ◽  
Author(s):  
Mahmoud Ramadan Elkazzaz ◽  
Amr kamel khalil Ahmed
Keyword(s):  
Retinoic Acid ◽  
Breast Milk ◽  
Docosahexaenoic Acid ◽  
Binding Affinity ◽  
Active Sites ◽  
Severe Disease ◽  
Gastrointestinal Symptoms ◽  
Influenza Viruses ◽  
Severe Illness ◽  
Cytokine Storm

Abstract SARS-CoV-2, which causes COVID-19, is a new virus that has spread fast over the world. The severity of COVID-19 at different ages has been a notable and constant observation: severity, the requirement for hospitalization, and mortality all grow sharply with age, although severe disease and death are uncommon in children and young adults.. The majority of children infected with SARS-CoV-2 are asymptomatic or have moderate symptoms, which include fever, cough, pharyngitis, gastrointestinal symptoms, and changes in taste and smell. The question of whether children are less likely to be infected with SARS-CoV-2 is still being debated. Children make up only 1 to 2% of all SARS-CoV-2 cases, according to large epidemiological research. these numbers are heavily, depend on testing criteria, and in many reports, testing was limited to those who were symptomatic or required hospitalization, which is less common in children.. According to certain research, children are just as likely as adults to contract SARS-CoV-2.9. Recent research suggests that children are less likely to become infected after coming into touch with a SARS-CoV-2-positive person.According to some reports, children and adolescents have similar virus loads and are hence just as likely to transmit SARS-CoV-2 as adults. Furthermore, the viral load in asymptomatic and symptomatic people may be identical. Reassuringly, transmission of the virus from children to other children or adults in schools has been infrequent.Children are less likely to be infected with SARS-CoV-2 and have less severe symptoms, which is similar to what has been observed with SARS-CoV-1 and Middle East respiratory disease (MERS)-CoV. Infection with most other respiratory viruses (e.g., respiratory syncytial virus (RSV), metapneumovirus, parainfluenza, or influenza viruses), on the other hand, has a far higher prevalence and severity in youngsters. Dr. Mahmoud Elkazzaz and Dr Amr kamel khalil Ahmed, the lead investigators of this observational study, recently published a preprint that demonstrated Docosahexaenoic acid (DHA) had a high binding affinity and greatest interactions with ACE2 active sites, as well as a moderate binding affinity and moderate interactions with the active sites of IL-6. The Docosahexaenoic acid (DHA) interacts with different active sites of IL6 and ACE2 which are involved in direct or indirect contacts with the ACE2 and IL-6 receptors which might act as potential blockers of functional ACE2 and IL-6 receptor complex.. A study proposed, a clinical benefit of targeting IL-17A signaling and the synergic inflammatory cytokine IL-6 to manage COVID-19 patients, particularly those presenting with cytokine storm syndrome.Hypercytokinemia, caused by notably high pro-inflammatory cytokines such as interleukin (IL)-1B, IL-6, IL-8, and IL-17, is mostly linked to the worsened clinical presentation of COVID-19 patients(14). In PBMCs from individuals with relapsing-remitting multiple sclerosis, a combination of docosahexaenoic acid (DHA) and all-trans-retinoic acid (ATRA) inhibits IL-17 gene expression.ConclusionsDocosahexaenoic acid (DHA) was detected in abundance in breast milk and other algal sources milk supplement used for newborns and children's feeding. As a result, we believe that docosahexaenoic acid (DHA) may protect children and newborns thorough competing with COVID-19 for ACE2 receptors and inhibiting IL-6 activity and may possibly help them avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS- CoV-2 RBD attachment to ACE2. In addition to IL-17 was fond to increase COVID-19 inflammatory complication in this case DHA combined with retinoic acid is expected to be effective in inhibiting IL-6 and IL-17.

scholarly journals Determination of the range in binding-site densities of rat skin heparin chains with high binding affinities for antithrombin

1988 ◽  
Vol 251 (1) ◽  
pp. 141-145 ◽  
Author(s):  
A A Horner ◽  
M Kusche ◽  
U Lindahl ◽  
C B Peterson
Keyword(s):  
Chemical Analysis ◽  
Binding Site ◽  
Binding Affinity ◽  
Intrinsic Fluorescence ◽  
Binding Affinities ◽  
Rat Skin ◽  
High Binding ◽  
Site Density ◽  
High Binding Affinity

Rat skin heparin proteoglycans vary markedly in the proportions of their constituent polysaccharide chains that have high binding affinity for antithrombin. As the proportion of such chains in a proteoglycan rises, their degree of affinity for antithrombin also increases [Horner (1987) Biochem. J. 244, 693-698]. The antithrombin-binding-site densities of such chains have now been determined, by measuring heparin-induced enhancement of the intrinsic fluorescence of antithrombin and by chemical analysis for the disaccharide sequence glucuronosyl-N-sulphoglucosaminyl (3,6-di-O-sulphate), which is unique to this site in heparin [Lindahl, Bäckström, Thunberg & Leder (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 6551-6555]. Antithrombin-binding-site density ranged from one to five sites per chain.

scholarly journals Immunoinformatics Prediction of Epitope Based Peptide Vaccine Against Listeria Monocytogenes Fructose Bisphosphate Aldolase Protein

2019 ◽  
Author(s):  
Mustafa Elhag ◽  
Mustafa Abubaker ◽  
Nagla Mohammad Ahmad ◽  
Esraa Musa Haroon ◽  
Ruaa Mohamed Alaagib ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Binding Affinity ◽  
3D Structure ◽  
Peptide Vaccine ◽  
Preventive Measure ◽  
Fructose Bisphosphate ◽  
High Binding ◽  
Life Threatening ◽  
Fructose 1,6 Bisphosphate ◽  
High Binding Affinity

AbstractListeria Monocytogenesrepresents an important food-borne pathogen worldwide that can cause life-threatening listeriosis disease especially in pregnant women, fetuses, elderly people, and immuno-compromised individuals with high mortality rates. Moreover, no vaccine against it exists. This study predicts an effective epitope-based vaccine against Fructose 1,6 Bisphosphate Aldolase (FBA) enzyme of Listeria Monocytogenes using immunoinformatics approaches. The sequences were retrieved from NCBI and several prediction tests were conducted to analyze possible epitopes for B-cell, T-cell MHC class I and II. 3D structure of the promising epitopes was obtained. Two epitopes showed high binding affinity for B-cells, while four epitopes showed high binding affinity for MHCI and MHCII. The results were promising to formulate a vaccine with more than 98% population coverage. We hope that these promising epitopes serves as a preventive measure for the disease in the future and recommend invivo and invitro studies.

Molecular docking study of Lens culinaris L. phytochemicals to NS3-NS2B protease of dengue virus serotype 2

2021 ◽  
Vol 1 (1) ◽  
pp. 26-37
Keyword(s):  
Molecular Docking ◽  
Binding Energy ◽  
Dengue Virus ◽  
Binding Affinity ◽  
Lens Culinaris ◽  
Binding Affinities ◽  
High Binding ◽  
Virus Serotype ◽  
Dengue Virus Serotype 2 ◽  
High Binding Affinity

Forty-three phytochemicals present in Lens culinaris were evaluated through in-silico molecular docking studies for their binding affinities to the NS2B-NS3 activator-protease complex of dengue virus serotype 2 (DENV-2). Among the various compounds tested, flavonoids (flavanols,favonols, proanthocyanidins, flavanones, flavones, and anthocyanins) demonstrated high binding affinities for the protease complex. Eriodictyol-7-O-rutinoside showed the least predicted binding energy at -9.1 kcal/mol followed by luteolin-7-O-glucoside at -8.8 kcal/mol. Glycosidic linkages appeared to enhance the binding affinities of flavonoids, aldohexoses being more potent than aldopentoses. Besides flavonoids, other classes of compounds demonstrating high binding affinities for the protease were carotenoids, phytosterols, and polyphenolic compounds like resveratrol and trans-resveratrol 3-O-b-glucoside (piceid), the latter showing predicted binding energy of -8.5 kcal/mol versus predicted binding energy of -7.2 kcal/mol for resveratrol. The 2D interactions of four high binding affinity compounds like eriodictyol, eriodictyol-7-O-rutinoside, catechin gallate, and luteolin-7-O-glucoside showed that all four compounds bound to the active site of the NS3 protease and not to the activator NS2B. Lys74 of NS3 was the common amino acid interacting with all four phytochemicals. Analysis of physicochemical properties of the compounds (Lipinski's Rule of 5) showed that the high binding affinity compounds have less than two violations, indicating that they can serve as useful lead compounds or as dengue virus serotype 2 therapeutics.

scholarly journals RaptRanker: in silico RNA aptamer selection from HT-SELEX experiment based on local sequence and structure information

2019 ◽  
Author(s):  
Ryoga Ishida ◽  
Tatsuo Adachi ◽  
Aya Yokota ◽  
Hidehito Yoshihara ◽  
Kazuteru Aoki ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Rna Aptamer ◽  
Binding Affinities ◽  
Affinity Reagents ◽  
Structure Information ◽  
High Binding ◽  
Local Sequence ◽  
Exponential Enrichment ◽  
High Binding Affinity

AbstractAptamers are short single-stranded RNA/DNA molecules that bind to specific target molecules. Aptamers with high binding-affinity and target specificity are identified using an in vitro procedure called high throughput systematic evolution of ligands by exponential enrichment (HT-SELEX). However, the development of aptamer affinity reagents takes a considerable amount of time and is costly because HT-SELEX produces a large dataset of candidate sequences, some of which have insufficient binding-affinity. Here, we present RNA aptamer Ranker (RaptRanker), a novel in silico method for identifying high binding-affinity aptamers from HT-SELEX data by scoring and ranking. RaptRanker analyzes HT-SELEX data by evaluating the nucleotide sequence and secondary structure simultaneously, and by ranking according to scores reflecting local structure and sequence frequencies. To evaluate the performance of RaptRanker, we performed two new HT-SELEX experiments, and evaluated binding affinities of a part of sequences that include aptamers with low binding-affinity. In both datasets, the performance of RaptRanker was superior to Frequency, Enrichment and MPBind. We also confirmed that the consideration of secondary structures is effective in HT-SELEX data analysis, and that RaptRanker successfully predicted the essential subsequence motifs in each identified sequence.

scholarly journals Herb-target virtual screening and network pharmacology for prediction of molecular mechanism of Danggui Beimu Kushen Wan for prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hong Li ◽  
Andrew Hung ◽  
Angela Wei Hong Yang
Keyword(s):  
Prostate Cancer ◽  
Binding Affinity ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Tight Binding ◽  
Experimental Studies ◽  
Network Pharmacology ◽  
High Morbidity ◽  
High Binding ◽  
High Binding Affinity

AbstractProstate cancer (PCa) is a cancer that occurs in the prostate with high morbidity and mortality. Danggui Beimu Kushen Wan (DBKW) is a classic formula for patients with difficult urination including PCa. This study aimed to investigate the molecular mechanisms of DBKW for PCa. We obtained DBKW compounds from our previous reviews. We identified potential targets for PCa from literature search, currently approved drugs and Open Targets database and filtered them by protein–protein interaction network analysis. We selected 26 targets to predict three cancer-related pathways. A total of 621 compounds were screened via molecular docking using PyRx and AutoDock Vina against 21 targets for PCa, producing 13041 docking results. The binding patterns and positions showed that a relatively small number of tight-binding compounds from DBKW were predicted to interact strongly and selectively with three targets. The top five high-binding-affinity compounds were selected to generate a network, indicating that compounds from all three herbs had high binding affinity against the 21 targets and may have potential biological activities with the targets. DBKW contains multi-targeting agents that could act on more than one pathway of PCa simultaneously. Further studies could focus on validating the computational results via experimental studies.

A fluorescent probe for butyrylcholinesterase activity in human serum based on a fluorophore with specific binding affinity for human serum albumin

2019 ◽  
Vol 55 (97) ◽  
pp. 14574-14577 ◽  
Author(s):  
Soyeon Yoo ◽  
Min Su Han
Keyword(s):  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Fluorescent Probe ◽  
Binding Affinity ◽  
Specific Binding ◽  
Turn On ◽  
High Binding ◽  
Butyrylcholinesterase Activity ◽  
High Binding Affinity

We report a novel turn-on sensing probe for the detection of butyrylcholinesterase activity in human serum using a fluorophore with high binding affinity for HSA.

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