scholarly journals Flexibility and mobility of SARS-CoV-2-related protein structures

2020 ◽  
Author(s):  
Rudolf A. Römer ◽  
Navodya S. Römer ◽  
A. Katrine Wallis
Keyword(s):  
In Silico ◽  
Drug Targets ◽  
Large Scale ◽  
Structural Information ◽  
Protein Structures ◽  
Antiviral Drug ◽  
Docking Studies ◽  
Related Protein

ABSTRACTThe worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of SARS-CoV-2 drug targets, i.e. SARS-CoV-2 protein structures as deposited on the Protein Databank (PDB). We study their flexibility, rigidity and mobility, an important first step in trying to ascertain their dynamics for further drug-related docking studies. We are using a recent protein flexibility modelling approach, combining protein structural rigidity with possible motion consistent with chemical bonds and sterics. For example, for the SARS-CoV-2 spike protein in the open configuration, our method identifies a possible further opening and closing of the S1 subunit through movement of SB domain. With full structural information of this process available, docking studies with possible drug structures are then possible in silico. In our study, we present full results for the more than 200 thus far published SARS-CoV-2-related protein structures in the PDB.

scholarly journals Flexibility and mobility of SARS-CoV-2-related protein structures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rudolf A. Römer ◽  
Navodya S. Römer ◽  
A. Katrine Wallis
Keyword(s):  
In Silico ◽  
Drug Targets ◽  
Large Scale ◽  
Structural Information ◽  
Protein Structures ◽  
Antiviral Drug ◽  
Docking Studies ◽  
Related Protein

AbstractThe worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of possible SARS-CoV-2 drug targets, as deposited on the Protein Databank (PDB), and ascertain their dynamics, flexibility and rigidity. For example, for the SARS-CoV-2 spike protein—using its complete homo-trimer configuration with 2905 residues—our method identifies a large-scale opening and closing of the S1 subunit through movement of the S$${}^\text{B}$$ B domain. We compute the full structural information of this process, allowing for docking studies with possible drug structures. In a dedicated database, we present similarly detailed results for the further, nearly 300, thus far resolved SARS-CoV-2-related protein structures in the PDB.

In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

2018 ◽  
Vol 21 (3) ◽  
pp. 215-221
Author(s):  
Haroon Khan ◽  
Muhammad Zafar ◽  
Helena Den-Haan ◽  
Horacio Perez-Sanchez ◽  
Mohammad Amjad Kamal
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
In Vivo Studies ◽  
In Vitro Assays ◽  
Chronic Obstructive ◽  
Lipoxygenase Inhibitors ◽  
Lipoxygenase Inhibition ◽  
In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

scholarly journals Oleuropein modulates over-proliferation of keratinocytes in mice with imiquimodmediated psoriasis and inhibits differentiation of TH17 cells through the JAK3/STAT3 axis

2020 ◽  
Author(s):  
Quan Shi ◽  
Qi He ◽  
Weiming Chen ◽  
Jianwen Long ◽  
Bo Zhang
Keyword(s):  
T Cells ◽  
In Silico ◽  
Th17 Cells ◽  
Skin Lesions ◽  
Docking Studies ◽  
Inflammatory Disorder ◽  
T Helper 17 ◽  
In Silico Docking

IntroductionOleuropein (OLP) is polyphenol obtained from olive oil; it is proved in Chinese traditional medicine for its use in disorders including autoimmune and inflammatory disorders. Psoriasis (PSR) is an autoimmune and inflammatory disorder triggered by T-helper-17 (Th17) cells.Material and methodsWe developed an imiquimod (IMQ)-mediated PSR model in mice to study the anti-inflammatory role of OLP in psoriasis. The mice were given 50 mg/kg and 100 mg/kg dose of OLP. Histology was done to assess the inflammation of lesions. Western blot analysis was done for JAK3/STAT3 in isolated T cells, expression of RORgt was done by RT-PCR. The In silico molecular docking studies were done for interaction of OLP with target protein STAT3 and JAK3.ResultsTreatment of OLP attenuated proliferation in IMQ-mediated keratinocytes, improved infiltration of CD3+ cells in the skin lesions and in CD4+ and CD8+ T cells and also ameliorated the levels of cytokines. In in vitro studies in isolated T cells, OLP blocked the differentiation of Th17 cells and also the levels of IL-17 and the JAK3/STAT3 pathway. The in silico docking showed that OLP had potential binding affinity with JAK3 and STAT3 which was parallel to in vivo and in vitro findings.ConclusionsOLP ameliorates psoriasis skin lesions by blocking Th17-mediated inflammation. OLP may be an interesting molecule for treating autoimmunity in psoriasis.

scholarly journals A Potential Peptide From Soy Cheese Produced Using Lactobacillus delbrueckii WS4 for Effective Inhibition of SARS-CoV-2 Main Protease and S1 Glycoprotein

2020 ◽  
Vol 7 ◽  
Author(s):  
Rounak Chourasia ◽  
Srichandan Padhi ◽  
Loreni Chiring Phukon ◽  
Md Minhajul Abedin ◽  
Sudhir P. Singh ◽  
...  
Keyword(s):  
Drug Targets ◽  
Docking Studies ◽  
Lactobacillus Delbrueckii ◽  
Amino Acid Residues ◽  
Main Protease ◽  
Effective Inhibition ◽  
Cheese Peptides ◽  
Potential Inhibitors

The COVID-19 pandemic caused by novel SARS-CoV-2 has resulted in an unprecedented loss of lives and economy around the world. In this study, search for potential inhibitors against two of the best characterized SARS-CoV-2 drug targets: S1 glycoprotein receptor-binding domain (RBD) and main protease (3CLPro), was carried out using the soy cheese peptides. A total of 1,420 peptides identified from the cheese peptidome produced using Lactobacillus delbrueckii WS4 were screened for antiviral activity by employing the web tools, AVPpred, and meta-iAVP. Molecular docking studies of the selected peptides revealed one potential peptide “KFVPKQPNMIL” that demonstrated strong affinity toward significant amino acid residues responsible for the host cell entry (RBD) and multiplication (3CLpro) of SARS-CoV-2. The peptide was also assessed for its ability to interact with the critical residues of S1 RBD and 3CLpro of other β-coronaviruses. High binding affinity was observed toward critical amino acids of both the targeted proteins in SARS-CoV, MERS-CoV, and HCoV-HKU1. The binding energy of KFVPKQPNMIL against RBD and 3CLpro of the four viruses ranged from −8.45 to −26.8 kcal/mol and −15.22 to −22.85 kcal/mol, respectively. The findings conclude that cheese, produced by using Lb. delbrueckii WS4, could be explored as a prophylactic food for SARS-CoV-2 and related viruses. In addition, the multi-target inhibitor peptide, which effectively inhibited both the viral proteins, could further be used as a terminus a quo for the in vitro and in vivo function against SARS-CoV-2.

scholarly journals Crambescin C1 Acts as A Possible Substrate of iNOS and eNOS Increasing Nitric Oxide Production and Inducing In Vivo Hypotensive Effect

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan A. Rubiolo ◽  
Emilio Lence ◽  
Concepción González-Bello ◽  
María Roel ◽  
José Gil-Longo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Active Site ◽  
In Silico ◽  
Hypotensive Effect ◽  
Docking Studies ◽  
No Production ◽  
Guanidine Alkaloids ◽  
Endogenous Substrate

Crambescins are guanidine alkaloids from the sponge Crambe crambe. Crambescin C1 (CC) induces metallothionein genes and nitric oxide (NO) is one of the triggers. We studied and compared the in vitro, in vivo, and in silico effects of some crambescine A and C analogs. HepG2 gene expression was analyzed using microarrays. Vasodilation was studied in rat aortic rings. In vivo hypotensive effect was directly measured in anesthetized rats. The targets of crambescines were studied in silico. CC and homo-crambescine C1 (HCC), but not crambescine A1 (CA), induced metallothioneins transcripts. CC increased NO production in HepG2 cells. In isolated rat aortic rings, CC and HCC induced an endothelium-dependent relaxation related to eNOS activation and an endothelium-independent relaxation related to iNOS activation, hence both compounds increase NO and reduce vascular tone. In silico analysis also points to eNOS and iNOS as targets of Crambescin C1 and source of NO increment. CC effect is mediated through crambescin binding to the active site of eNOS and iNOS. CC docking studies in iNOS and eNOS active site revealed hydrogen bonding of the hydroxylated chain with residues Glu377 and Glu361, involved in the substrate recognition, and explains its higher binding affinity than CA. The later interaction and the extra polar contacts with its pyrimidine moiety, absent in the endogenous substrate, explain its role as exogenous substrate of NOSs and NO production. Our results suggest that CC serve as a basis to develop new useful drugs when bioavailability of NO is perturbed.

New Benzodioxole-based Pyrazoline Derivatives: Synthesis and Anticandidal, In silico ADME, Molecular Docking Studies

2018 ◽  
Vol 16 (1) ◽  
pp. 82-92 ◽  
Author(s):  
Ahmet Özdemir ◽  
Belgin Sever ◽  
Mehlika Dilek Altıntop
Keyword(s):  
In Silico ◽  
Fungal Infections ◽  
Computational Study ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Heme Group ◽  
In Silico Studies ◽  
Nih 3T3

Background: Azoles are commonly used in the treatment and prevention of fungal infections. They suppress fungal growth by acting on the heme group of lanosterol 14α-demethylase enzyme (CYP51), thus blocking the biosynthesis of ergosterol. </P><P> Objectives: Due to the importance of pyrazolines in the field of antifungal drug design, we aimed to design and synthesize new pyrazoline-based anticandidal agents. Methods: New pyrazoline derivatives were synthesized via the reaction of 1-(chloroacetyl)-3-(2- thienyl)-5-(1,3-benzodioxol-5-yl)-2-pyrazoline with aryl thiols. These compounds were evaluated for their in vitro antifungal effects on Candida species. Docking studies were performed to predict the affinity of the most effective anticandidal agents to substrate binding site of CYP51. Furthermore, MTT assay was performed to determine the cytotoxic effects of the compounds on NIH/3T3 mouse embryonic fibroblast cell line. A computational study for the prediction of ADME properties of all compounds was also carried out. Results: Compounds 5, 8, 10 and 12 were found as the most potent anticandidal agents against Candida albicans and Candida glabrata in this series with the same MIC values of ketoconazole and they also exhibited low toxicity against NIH/3T3 cells. Docking results indicated that all these compounds showed good binding affinity into the active site of CYP51. In particular, chloro substituted compounds 8 and 12 bind to CYP51 through direct coordination with the heme group. According to in silico studies, compound 8 only violated one parameter of Lipinski’s rule of five, making it a potential orally bioavailable agent. Conclusion: Compound 8 was defined as a promising candidate for further in vitro and in vivo studies.

scholarly journals In Silico Analysis and Molecular Docking Studies of Plumbagin and Piperine Ligands as Potential Inhibitors of Alpha-Glucosidase Receptor

2020 ◽  
Vol 11 (2) ◽  
pp. 9629-9637
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Docking Studies ◽  
The Body ◽  
Insufficient Amount ◽  
In Silico Studies ◽  
Optimization Simulation ◽  
Alpha Glucosidase

In ’today’s generation, Diabetes mellitus is a very common lifestyle-based disease in which an insufficient amount of insulin is produced, which results in a rise of glucose level in the body with frequent urination and patient feels thirsty and hungry. In our present work, we have used the alpha-glucosidase receptor against the natural plant product as a ligand for docking studies. For this in silico studies, various online tools, databases, and software were used. The proposed approaches were PDB, Molinspiration, Chemsketch, PyRx software, and many more. The binding scores were retrieved by PyRx software and no tumorigenicity, mutagenicity was there, and all parameters were in the desired range. The compounds used as ligands have shown energy minimization up to -6.7 to -8.7 kcal and can be further used as optimization, simulation, and in vitro and in vivo experimental validation.

scholarly journals Naturally Available Flavonoid Aglycones as Potential Antiviral Drug Candidates against SARS-CoV-2

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6559
Author(s):  
Ahmed A. Al-Karmalawy ◽  
Mai M. Farid ◽  
Ahmed Mostafa ◽  
Alia Y. Ragheb ◽  
Sara H. Mahmoud ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Antiviral Drug ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Flavonoid Aglycones

Flavonoids are important secondary plant metabolites that have been studied for a long time for their therapeutic potential in inflammatory diseases because of their cytokine-modulatory effects. Five flavonoid aglycones were isolated and identified from the hydrolyzed aqueous methanol extracts of Anastatica hierochuntica L., Citrus reticulata Blanco, and Kickxia aegyptiaca (L.) Nabelek. They were identified as taxifolin (1), pectolinarigenin (2), tangeretin (3), gardenin B (4), and hispidulin (5). These structures were elucidated based on chromatographic and spectral analysis. In this study, molecular docking studies were carried out for the isolated and identified compounds against SARS-CoV-2 main protease (Mpro) compared to the co-crystallized inhibitor of SARS-CoV-2 Mpro (α-ketoamide inhibitor (KI), IC50 = 66.72 µg/mL) as a reference standard. Moreover, in vitro screening against SARS-CoV-2 was evaluated. Compounds 2 and 3 showed the highest virus inhibition with IC50 12.4 and 2.5 µg/mL, respectively. Our findings recommend further advanced in vitro and in vivo studies of the examined isolated flavonoids, especially pectolinarigenin (2), tangeretin (3), and gardenin B (4), either alone or in combination with each other to identify a promising lead to target SARS-CoV-2 effectively. This is the first report of the activity of these compounds against SARS-CoV-2.

scholarly journals Leishmania spp Epitopes in Humans Naturally Resistant to the Disease: Working Toward a Synthetic Vaccine

2021 ◽  
Vol 11 ◽  
Author(s):  
Magda Melissa Flórez ◽  
Rocío Rodríguez ◽  
José Antonio Cabrera ◽  
Sara M. Robledo ◽  
Gabriela Delgado
Keyword(s):  
Immune Response ◽  
In Silico ◽  
Large Scale ◽  
Mononuclear Cells ◽  
Clinical Symptoms ◽  
Epitope Prediction ◽  
Effective Vaccine ◽  
Peripheral Blood Mononuclear

Vaccines are one of the most effective strategies to fight infectious diseases. Reverse vaccinology strategies provide tools to perform in silico screening and a rational selection of potential candidates on a large scale before reaching in vitro and in vivo evaluations. Leishmania infection in humans produces clinical symptoms in some individuals, while another part of the population is naturally resistant (asymptomatic course) to the disease, and therefore their immune response controls parasite replication. By the identification of epitopes directly in humans, especially in those resistant to the disease, the probabilities of designing an effective vaccine are higher. The aim of this work was the identification of Leishmania epitopes in resistant humans. To achieve that, 11 peptide sequences (from Leishmania antigenic proteins) were selected using epitope prediction tools, and then, peripheral blood mononuclear cells (PBMCs) were isolated from human volunteers who were previously divided into four clinical groups: susceptible, resistant, exposed and not exposed to the parasite. The induction of inflammatory cytokines and lymphoproliferation was assessed using monocyte-derived dendritic cells (moDCs) as antigen-presenting cells (APCs). The response was evaluated after exposing volunteers’ cells to each peptide. As a result, we learned that STI41 and STI46 peptides induced IL-8 and IL-12 in moDCs and lymphoproliferation and low levels of IL-10 in lymphocytes differentially in resistant volunteers, similar behavior to that observed in those individuals to L. panamensis lysate antigens. We conclude that, in silico analysis allowed for the identification of natural Leishmania epitopes in humans, and also STI41 and STI46 peptides could be epitopes that lead to a cellular immune response directed at parasite control.

1,3,5-Pyrazoline Derivatives in CNS Disorders: Synthesis, Biological Evaluation and Structural Insights through Molecular Docking

2020 ◽  
Vol 19 (6) ◽  
pp. 448-465
Author(s):  
Himanshi Sharma ◽  
Pooja A. Chawla ◽  
Rohit Bhatia
Keyword(s):  
In Silico ◽  
Antidepressant Activity ◽  
Tail Suspension Test ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Hydroxyl Group ◽  
Spectral Techniques ◽  
Lipinski’S Rule

Background: Anxiety and oxidative stress are the common disorders prevailing in the modern age. Many new pyrazoline derivatives have been synthesized and patented, but there is still continuous research in progress to explore antidepressant and antioxidant potential of pyrazoline scaffold. Objective: The present work was carried out to synthesize, characterize and evaluate the pharmacological potential of 1,3,5-Pyrazoline derivatives. Methods: Ten new 1,3,5-Pyrazoline derivatives were synthesized and characterized by IR, 1HNMR and mass spectral techniques. The synthesized pyrazoline derivatives were investigated for their in vivo antidepressant activity by Tail Suspension Test (TST) and in vitro antioxidant activity by FRAP and DPPH assay methods. The docking studies and in silico ADME and toxicity characteristics were also evaluated. Results: Among the synthesized analogues, IVh showed the highest antidepressant activity with a significant reduction in the duration of immobility. The compound IVh emerged as the most potent antioxidant compound due to the presence of an electron releasing hydroxyl group. Docking studies of most potent compounds revealed good interaction points with the MAO-A enzyme. The compounds were found to obey Lipinski’s Rule of Five and displayed the least in silico toxicity profile. Conclusion: The synthesized compounds were found to possess great potential in decreasing the duration of immobility in Swiss albino mice and scavenging free radicals. These compounds may serve as new leads for further drug exploration.

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