scholarly journals Description of a Novel Fameshifting Site in the 5'UTR of SARS-CoV-2 as a Potential Drug Target

2021 ◽  
Author(s):  
Emilio Garcia-Moran ◽  
Marta Hernandez ◽  
David Abad ◽  
Jose Maria Eiros
Keyword(s):  
Secondary Structure ◽  
Drug Target ◽  
3D Structure ◽  
Oral Drugs ◽  
Bioinformatic Tools ◽  
Lead Compounds ◽  
The World ◽  
Positive Sense ◽  
Potential Regulatory Role

Abstract SARS-CoV-2 is an enveloped positive-sense single-stranded RNA coronavirus that causes COVID-19 whose present outbreak has cost a high number of casualties throughout the world. The aim of this work was to scan the SARS-CoV-2 genome in search for new therapeutic targets. We found a sequence in the 5'UTR (NC 045512:74-130), consisting of a typical heptamer next to a structured region that may cause frameshifting. The potential biological value of this region is shown by its similarity with other coronaviruses related with SARS-CoV and its sequence conservation within isolates from SARS-CoV-2. We have predicted the secondary structure of the region by means of different bioinformatic tools. We have chosen a probable secondary structure to proceed with a 3D reconstruction of the structured segment. We carried out virtual docking on the 3D structure to look for a binding site and then for drug ligands from a database of lead compounds. Several molecules that would probably administered as oral drugs show promising binding affinity within the structured region and so it would be possible interfere the potential regulatory role of our sequence of interest.

scholarly journals Putative Secondary Structure at 5’UTR as a Potential Antiviral Target against SARS-CoV-2

2021 ◽  
Author(s):  
Emilio Garcia-Moran ◽  
Marta Hernández ◽  
David Abad ◽  
José M. Eiros
Keyword(s):  
Secondary Structure ◽  
3D Structure ◽  
Oral Drugs ◽  
Ribosomal Frameshifting ◽  
Bioinformatic Tools ◽  
Lead Compounds ◽  
Positive Sense ◽  
High Sequence Conservation ◽  
Current Outbreak ◽  
Potential Regulatory Role

SARS-CoV-2 is an enveloped positive-sense single-stranded RNA coronavirus that causes COVID-19, of which the current outbreak has resulted in a high number of cases and fatalities throughout the world, even vaccine doses are being administered. The aim of this work was to scan the SARS-CoV-2 genome in search for therapeutic targets. We found a sequence in the 5’UTR (NC 045512:74-130), consisting of a typical heptamer next to a structured region that may cause ribosomal frameshifting. The potential biological value of this region is relevant through its low similarity with other viruses, including coronaviruses related to SARS-CoV, and its high sequence conservation within multiple SARS-CoV-2 isolates. We have predicted the secondary structure of the region by means of different bioinformatic tools. We have suggested a most probable secondary structure to proceed with a 3D reconstruction of the structured segment. Finally, we carried out virtual docking on the 3D structure to look for a binding site and then for drug ligands from a database of lead compounds. Several molecules that could be probably administered as oral drugs show promising binding affinity within the structured region, and so it could be possible interfere its potential regulatory role.

scholarly journals Binding site identification of COVID-19 main protease 3D structure by homology modeling

2021 ◽  
Vol 21 (3) ◽  
pp. 1713
Author(s):  
Marion Adebiyi ◽  
Oludayo O. Olugbara
Keyword(s):  
Secondary Structure ◽  
Homology Modeling ◽  
Binding Site ◽  
Drug Target ◽  
3D Structure ◽  
Random Coil ◽  
Local Alignment ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Main Protease

The influx of coronavirus in 2019 (COVID-19) from Wuhan of China has led to a global pandemic, undesirable hiatus, and recorded millions of infection cases with several deaths worldwide. The strain of COVID-19 has neither known treatments nor vaccines, but recent studies have shown that a few of its enzymes may have been considered as potential drug target. Since its influx, the virus has been well-studied, but a lot is not known about its protease yet.  The purpose of this work was to identify the binding site in-silico and present 3D structure of COVID-19 main protease (Mpro) by homology modeling through multiple alignment followed by optimization and validation. The modeling was done by Swiss-Model template library and basic local alignment search tool (BLAST). The obtained homotrimer oligo-state model was verified for reliability using structural validation software such as PROCHECK, Verify3D, MolProbity and QMEAN. The HHBlits software was used to determine the structures that matched the target sequence by evolution. Best template, 6u7h.1.A was used to build a tertiary structure for Mpro with ProMod3 3.0.0 on the Swiss-Model workspace. Self-optimized prediction method with alignment (SOPMA) was applied to compute features of the secondary structure. The verification of quality of COVID-19 structure through Ramachandran plot showed an abundance of 99.3% of amino acid residues in allowed regions while 0.1% in disallowed region. The Verify3D rated the structure a 90.87% PASS of residues having an average 3D-1D score of at least 0.2, which validates a good environment profile for the COVID-19 Mpro model. The features of the secondary structure indicated that the modeled 3D structure of Mpro contains 32.05% α-helix and 37.17% random coil with 25.92 extended strand. DeepSite algorithm elucidates the binding site area that captured local patterns in the structure and exposed the surface cavity of the binding pocket of this protein. The main result of this study suggests that blocking expression of the protein may constitute an efficient approach for transmission blockage. Hence, our thought is that Mpro of COVID-19 may be considered a potential drug target. Nevertheless, more experimental analyses, verification and validation experiments will be required as a targeted drug or vaccine design against COVID-19 virus.

scholarly journals Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

2021 ◽  
Author(s):  
Abhisek Dwivedy ◽  
Richard Mariadasse ◽  
Mohammed Ahmad ◽  
Sayan Chakraborty ◽  
Deepsikha Kar ◽  
...  
Keyword(s):  
Active Site ◽  
Drug Target ◽  
Kinase Inhibitors ◽  
3D Structure ◽  
Drug Repurposing ◽  
Lead Compounds ◽  
Nucleotidyl Transferase ◽  
Domain Organisation ◽  
First Time

AbstractApart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness as well as DFT properties. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, the proposed kinase inhibitors and a few of the predicted nucleotidyl transferase inhibitors significantly inhibited the aforementioned enzymatic activity. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

scholarly journals Identification of New BMP6 Pro-Peptide Mutations in Patients with Unexplained Iron-Overload

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 264-264
Author(s):  
Chiara Piubelli ◽  
Annalisa Castagna ◽  
Giacomo Marchi ◽  
Monica Rizzi ◽  
Fabiana Busti ◽  
...  
Keyword(s):  
Iron Overload ◽  
Conflicts Of Interest ◽  
Late Onset ◽  
Hereditary Hemochromatosis ◽  
3D Structure ◽  
Potential Candidate ◽  
Missense Mutations ◽  
Tertiary Referral Centre ◽  
Bioinformatic Tools

Abstract Background: Hereditary Hemochromatosis (HH) is a genetically heterogeneous disorder caused by mutations in at least 5 different genes (HFE, HJV, TFR2, SLC40A1, and HAMP) involved in the production and function of the liver hormone hepcidin, a key regulator of iron metabolism. Nevertheless, patients with a HH-like phenotype that remains unexplained, despite extensive sequencing of the known genes, are not infrequently seen at referral centres, implicating the role of still unknown genetic factors. A compelling candidate is Bone Morphogenetic Protein 6 (BMP6), a member of TGFb superfamily, whose expression is stimulated by increased iron stores in the liver. BMP6 acts as a major activator of the BMP-SMAD signalling pathway, ultimately leading to the upregulation of hepcidin gene transcription. Indeed, early this year French Authors have described 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with mild to moderate, late onset, unexplained iron overload (Daher R, Gastroenterology 2016). Methods: we recently updated our next generation sequencing (NGS)-based second level genetic test for the molecular diagnosis of non-HFE HH (Badar S, Am J Hematol 2016), by adding a number of novel potential candidate genes, including BMP6, to the panel of the 5 known HH genes. This test was applied to 38 patients evaluated at our tertiary referral centre for iron disorders, because of an unexplained iron overload phenotype. Results: we found 3 heterozygous missense mutations in BMP6 gene in 4 patients with unexplained, late-onset, iron overload, from 3 different families. Their relevant clinical data are summarized into Table 1. Of note, 1 mutation (p.Leu96Pro) was the same recently described by Daher et al. and proven to be functional. The other two mutations (p.Glu112Gln, p.Arg257His) were novel, predicted damaging by bioinformatic tools, and both located in the pro-peptide domain, known to be crucial for appropriate BMP6 processing and secretion. They were further studied by in silico modelling, based on the available 3D structure of the TGFb, which also resulted to be consistent with their pathogenetic role. Conclusions: to the best of our knowledge, our results provide the first independent confirmation of the likely causal role of BMP6 mutations in late onset, moderate iron overload phenotype, unrelated to mutations in the established 5 HH genes. Disclosures No relevant conflicts of interest to declare.

New Aspects of Monoamine Oxidase B Inhibitors: The Key Role of Halogens to Open the Golden Door

2020 ◽  
Vol 28 (2) ◽  
pp. 266-283 ◽  
Author(s):  
Bijo Mathew ◽  
Simone Carradori ◽  
Paolo Guglielmi ◽  
Md. Sahab Uddin ◽  
Hoon Kim
Keyword(s):  
Monoamine Oxidase ◽  
Drug Target ◽  
Halogen Bonds ◽  
Target Interaction ◽  
Lead Compounds ◽  
Structure Activity ◽  
Pharmacodynamic Profile ◽  
The Impact ◽  
Important Enzyme

A large plethora of drugs and promising lead compounds contain halogens in their structures. The introduction of such moieties strongly modulates their physical-chemical features as well as pharmacokinetic and pharmacodynamic profile. The most important outcome was shown to be the ability of these halogens to favourably influence the drug-target interaction and energetic stability within the active site by the establishment of halogen bonds. This review attempted to demonstrate the key role exerted by these versatile moieties when correctly located in an organic scaffold to display Monoamine Oxidase (MAO) inhibition and selectivity towards the B isoform of this important enzyme. Human MAOs are well-recognized as therapeutic targets for mood disorders and neurodegenerative diseases and medicinal chemists were prompted to discover the structural requirements crucial to discriminate the slight differences between the active sits of the two isoforms (MAO-A and MAOB). The analysis of the structure-activity relationships of the most important scaffolds (hydrazothiazoles, coumarins, chromones, chalcones, pyrazolines) and the impact of halogen (F, Cl, Br and I) insertion on this biological activity and isozyme selectivity have been reported being a source of inspiration for the medicinal chemists.

scholarly journals Drug discovery in leishmaniasis using protein lipidation as a target

2021 ◽  
Author(s):  
James A. Brannigan ◽  
Anthony J. Wilkinson
Keyword(s):  
High Throughput Screening ◽  
Drug Target ◽  
Leishmania Donovani ◽  
Covalent Modification ◽  
High Morbidity ◽  
Lead Compounds ◽  
Frontline Treatment ◽  
The Stability ◽  
Substrate Proteins

AbstractThe leishmaniases are infectious diseases caused by a number of species of obligate intracellular protozoa of the genus Leishmania with disease manifesting as cutaneous, mucocutaneous and visceral forms. Despite being endemic in more than 80 countries and its being the cause of high morbidity and mortality, leishmaniasis remains a neglected tropical disease. Chemotherapy is the frontline treatment, but drugs in current use suffer from toxic side effects, difficulties in administration and extended treatment times — moreover, resistance is emerging. New anti-leishmanial drugs are a recognised international priority. Here, we review investigations into N-myristoyltransferase (NMT) as a potential drug target. NMT catalyses the co-translational transfer of a C14 fatty acid from myristoyl-CoA onto the N-terminal glycine residue of a significant subset of proteins in eukaryotic cells. This covalent modification influences the stability and interactions of substrate proteins with lipids and partner proteins. Structure-guided development of new lead compounds emerging from high-throughput screening campaigns targeting Leishmania donovani NMT has led to the discovery of potent inhibitors which have been used to gain insights into the role of protein myristoylation in these parasites and to validate NMT as a drug target.

The essence and causes of the spiritual and moral decline of mankind in the XX century

1998 ◽  
pp. 124-127
Author(s):  
V. Tolkachenko
Keyword(s):  
Well Being ◽  
Religious Institutions ◽  
Social Force ◽  
The World ◽  
Role Of Religion

One of the most important reasons for such a clearly distressed state of society was the decline of religion as a social force, the external manifestation of which is the weakening of religious institutions. "Religion," Baha'u'llah writes, "is the greatest of all means of establishing order in the world to the universal satisfaction of those who live in it." The weakening of the foundations of religion strengthened the ranks of ignoramuses, gave them impudence and arrogance. "I truly say that everything that belittles the supreme role of religion opens way for the revelry of maliciousness, inevitably leading to anarchy. " In another Tablet, He says: "Religion is a radiant light and an impregnable fortress that ensures the safety and well-being of the peoples of the world, for God-fearing induces man to adhere to the good and to reject all evil." Blink the light of religion, and chaos and distemper will set in, the radiance of justice, justice, tranquility and peace. "

The problem of periodization of the history of religion

1997 ◽  
pp. 3-8
Author(s):  
Borys Lobovyk
Keyword(s):  
Religious Studies ◽  
Human Being ◽  
Religious Development ◽  
History Of Religion ◽  
The Social ◽  
The World ◽  
History Of ◽  
Role Of Religion

An important problem of religious studies, the history of religion as a branch of knowledge is the periodization process of the development of religious phenomenon. It is precisely here, as in focus, that the question of the essence and meaning of the religious development of the human being of the world, the origin of beliefs and cult, the reasons for the changes in them, the place and role of religion in the social and spiritual process, etc., are converging.

External Factors of Big Business Transformation in Russia

2005 ◽  
pp. 72-89 ◽  
Author(s):  
Ya. Pappe ◽  
Ya. Galukhina
Keyword(s):  
Financial Market ◽  
Capital Market ◽  
Business Groups ◽  
External Factors ◽  
Big Business ◽  
Business Transformation ◽  
Global Standards ◽  
The World ◽  
Principal Subject

The paper is devoted to the role of the global financial market in the development of Russian big business. It proves that terms and standards posed by this market as well as opportunities it offers determine major changes in Russian big business in the last three years. The article examines why Russian companies go abroad to attract capital and provides data, which indicate the scope of this phenomenon. It stresses the effects of Russian big business’s interaction with the world capital market, including the modification of the principal subject of Russian big business from integrated business groups to companies and the changes in companies’ behavior: they gradually move away from the so-called Russian specifics and adopt global standards.

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