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Structural and Drug Screening Analysis of the Non-structural Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 Virus Extracted From Indian Coronavirus Disease 2019 Patients.

ABSTRACT: The novel coronavirus 2 (nCoV2) outbreaks took place in December 2019 in Wuhan City, Hubei Province, China. It continued to spread worldwide in an unprecedented manner, bringing the whole world to a lockdown and causing severe loss of life and economic stability. The coronavirus disease 2019 (COVID-19) pandemic has also affected India, infecting more than 10 million till 31st December 2020 and resulting in more than a hundred thousand deaths. In the absence of an effective vaccine, it is imperative to understand the phenotypic outcome of the genetic variants and subsequently the mode of action of its proteins with respect to human proteins and other bio-molecules. Availability of a large number of genomic and mutational data extracted from the nCoV2 virus infecting Indian patients in a public repository provided an opportunity to understand and analyze the specific variations of the virus in India and their impact in broader perspectives. Non-structural proteins (NSPs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) virus play a major role in its survival as well as virulence power. Here, we provide a detailed overview of the SARS-CoV2 NSPs including primary and secondary structural information, mutational frequency of the Indian and Wuhan variants, phylogenetic profiles, three-dimensional (3D) structural perspectives using homology modeling and molecular dynamics analyses for wild-type and selected variants, host-interactome analysis and viral-host protein complexes, and in silico drug screening with known antivirals and other drugs against the SARS-CoV2 NSPs isolated from the variants found within Indian patients across various regions of the country. All this information is categorized in the form of a database named, Database of NSPs of India specific Novel Coronavirus (DbNSP InC), which is freely available at http://www.hpppi.iicb.res.in/covid19/index.php.

SUBMITTER: Biswas N

PROVIDER: S-EPMC7985531 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The purpose of this study was to examine the deltoid skin biopsy in twenty-three patients with coronavirus disease 2019 (COVID-19), most severely ill, for vascular complement deposition and correlate this with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA and protein localization and ACE2 expression. Deltoid skin microvascular complement screening has been applied to patients with various systemic complement-mediated microvascular syndromes, best exemplified by atypical hemolytic uremic syndrome. In 21 of 23 cases, substantial microvascular deposition of complement components was identified. The two patients without significant complement deposition included one patient with moderate disease and a severely ill patient who although on a ventilator for a day was discharged after 3 days. The dominant microvascular complement immunoreactant identified was the terminal membranolytic attack complex C5b-9. Microvascular complement deposition strongly colocalized in situ with the SARS-CoV-2 viral proteins including spike glycoproteins in the endothelial cells as well as the viral receptor ACE2 in lesional and nonlesional skin; viral RNA was not evident. Microvascular SARS-CoV-2 viral protein, complement, and ACE2 expression was most conspicuous in the subcutaneous fat. Although the samples from severely ill patients with COVID-19 were from grossly normal skin, light microscopically focal microvascular abnormalities were evident that included endothelial cell denudement, basement membrane zone reduplication, and small thrombi. It is concluded that complement activation is common in grossly normal skin, especially in the subcutaneous fat which may provide a link between severe disease and obesity, in people with severe COVID-19, and the strong colocalization with the ACE2 receptor and viral capsid proteins without viral RNA suggests that circulating viral proteins (ie, pseudovirions) may dock onto the endothelial of these microvessels and induce complement activation.

Project description:A novel coronavirus, called 2019-nCoV, was recently found in Wuhan, Hubei Province of China, and now is spreading across China and other parts of the world. Although there are some drugs to treat 2019-nCoV, there is no proper scientific evidence about its activity on the virus. It is of high significance to develop a drug that can combat the virus effectively to save valuable human lives. It usually takes a much longer time to develop a drug using traditional methods. For 2019-nCoV, it is now better to rely on some alternative methods such as deep learning to develop drugs that can combat such a disease effectively since 2019-nCoV is highly homologous to SARS-CoV. In the present work, we first collected virus RNA sequences of 18 patients reported to have 2019-nCoV from the public domain database, translated the RNA into protein sequences, and performed multiple sequence alignment. After a careful literature survey and sequence analysis, 3C-like protease is considered to be a major therapeutic target and we built a protein 3D model of 3C-like protease using homology modeling. Relying on the structural model, we used a pipeline to perform large scale virtual screening by using a deep learning based method to accurately rank/identify protein-ligand interacting pairs developed recently in our group. Our model identified potential drugs for 2019-nCoV 3C-like protease by performing drug screening against four chemical compound databases (Chimdiv, Targetmol-Approved_Drug_Library, Targetmol-Natural_Compound_Library, and Targetmol-Bioactive_Compound_Library) and a database of tripeptides. Through this paper, we provided the list of possible chemical ligands (Meglumine, Vidarabine, Adenosine, D-Sorbitol, D-Mannitol, Sodium_gluconate, Ganciclovir and Chlorobutanol) and peptide drugs (combination of isoleucine, lysine and proline) from the databases to guide the experimental scientists and validate the molecules which can combat the virus in a shorter time.

Dataset Information

Structural and Drug Screening Analysis of the Non-structural Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 Virus Extracted From Indian Coronavirus Disease 2019 Patients.

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