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      Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes

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          Abstract

          Introduction

          COVID-19 cases are on surge; however, there is no efficient treatment or vaccine that can be used for its management. Numerous clinical trials are being reviewed for use of different drugs, biologics, and vaccines in COVID-19. A much empirical approach will be to repurpose existing drugs for which pharmacokinetic and safety data are available, because this will facilitate the process of drug development. The article discusses the evidence available for the use of Ivermectin, an anti-parasitic drug with antiviral properties, in COVID-19.

          Methods

          A rational review of the drugs was carried out utilizing their clinically significant attributes. A more thorough understanding was met by virtual embodiment of the drug structure and realizable viral targets using artificial intelligence (AI)-based and molecular dynamics (MD)-simulation-based study.

          Conclusion

          Certain studies have highlighted the significance of ivermectin in COVID-19; however, it requires evidences from more Randomised Controlled Trials (RCTs) and dose- response studies to support its use. In silico-based analysis of ivermectin’s molecular interaction specificity using AI and classical mechanics simulation-based methods indicates positive interaction of ivermectin with viral protein targets, which is leading for SARS-CoV 2 N-protein NTD (nucleocapsid protein N-terminal domain).

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          Most cited references35

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          The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro

          Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
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            Is Open Access

            I-TASSER server for protein 3D structure prediction

            Yang Zhang (2008)
            Background Prediction of 3-dimensional protein structures from amino acid sequences represents one of the most important problems in computational structural biology. The community-wide Critical Assessment of Structure Prediction (CASP) experiments have been designed to obtain an objective assessment of the state-of-the-art of the field, where I-TASSER was ranked as the best method in the server section of the recent 7th CASP experiment. Our laboratory has since then received numerous requests about the public availability of the I-TASSER algorithm and the usage of the I-TASSER predictions. Results An on-line version of I-TASSER is developed at the KU Center for Bioinformatics which has generated protein structure predictions for thousands of modeling requests from more than 35 countries. A scoring function (C-score) based on the relative clustering structural density and the consensus significance score of multiple threading templates is introduced to estimate the accuracy of the I-TASSER predictions. A large-scale benchmark test demonstrates a strong correlation between the C-score and the TM-score (a structural similarity measurement with values in [0, 1]) of the first models with a correlation coefficient of 0.91. Using a C-score cutoff > -1.5 for the models of correct topology, both false positive and false negative rates are below 0.1. Combining C-score and protein length, the accuracy of the I-TASSER models can be predicted with an average error of 0.08 for TM-score and 2 Å for RMSD. Conclusion The I-TASSER server has been developed to generate automated full-length 3D protein structural predictions where the benchmarked scoring system helps users to obtain quantitative assessments of the I-TASSER models. The output of the I-TASSER server for each query includes up to five full-length models, the confidence score, the estimated TM-score and RMSD, and the standard deviation of the estimations. The I-TASSER server is freely available to the academic community at .
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              BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities

              BindingDB () is a publicly accessible database currently containing ∼20 000 experimentally determined binding affinities of protein–ligand complexes, for 110 protein targets including isoforms and mutational variants, and ∼11 000 small molecule ligands. The data are extracted from the scientific literature, data collection focusing on proteins that are drug-targets or candidate drug-targets and for which structural data are present in the Protein Data Bank. The BindingDB website supports a range of query types, including searches by chemical structure, substructure and similarity; protein sequence; ligand and protein names; affinity ranges and molecular weight. Data sets generated by BindingDB queries can be downloaded in the form of annotated SDfiles for further analysis, or used as the basis for virtual screening of a compound database uploaded by the user. The data in BindingDB are linked both to structural data in the PDB via PDB IDs and chemical and sequence searches, and to the literature in PubMed via PubMed IDs.
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                Author and article information

                Contributors
                drbikashus@yahoo.com
                Journal
                Pharmacol Rep
                Pharmacol Rep
                Pharmacological Reports
                Springer International Publishing (Cham )
                1734-1140
                2299-5684
                3 January 2021
                : 1-14
                Affiliations
                GRID grid.415131.3, ISNI 0000 0004 1767 2903, Department of Pharmacology, , Post Graduate Institute of Medical Education and Reseasrch (PGIMER), ; Chandigarh, 160012 India
                Author information
                http://orcid.org/0000-0002-4017-641X
                Article
                195
                10.1007/s43440-020-00195-y
                7778723
                33389725
                07606b64-3042-4102-b67d-b3dfe6d569ec
                © Maj Institute of Pharmacology Polish Academy of Sciences 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 29 September 2020
                : 9 November 2020
                : 12 November 2020
                Categories
                Review

                ivermectin,covid-19,sars-cov-2,treatment
                ivermectin, covid-19, sars-cov-2, treatment

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