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      Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1)

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          Abstract

          Non-structural protein 1 (nsp1) is found in all Betacoronavirus genus, an important viral group that causes severe respiratory human diseases. This protein has significant role in pathogenesis and it is considered a probably major virulence factor. As it is absent in humans, it becomes an interesting target of study, especially when it comes to the rational search for drugs, since it increases the specificity of the target and reduces possible adverse effects that may be caused to the patient. Using approaches in silico we seek to study the behavior of nsp1 in solution to obtain its most stable conformation and find possible drugs with affinity to all of them. For this purpose, complete model of nsp1 of SARS-CoV-2 were predicted and its stability analyzed by molecular dynamics simulations in five different replicas. After main pocket validation using two control drugs and the main conformations of nsp1, molecular docking based on virtual screening were performed to identify novel potential inhibitors from DrugBank database. It has been found 16 molecules in common to all five nsp1 replica conformations. Three of them was ranked as the best compounds among them and showed better energy score than control molecules that have in vitro activity against nsp1 from SARS-CoV-2. The results pointed out here suggest new potential drugs for therapy to aid the rational drug search against COVID-19.

          Communicated by Ramaswamy H. Sarma

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          Most cited references25

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          Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle

          Since December 2019, a total of 41 cases of pneumonia of unknown etiology have been confirmed in Wuhan city, Hubei Province, China. Wuhan city is a major transportation hub with a population of more than 11 million people. Most of the patients visited a local fish and wild animal market last month. At a national press conference held today, Dr Jianguo Xu, an academician of the Chinese Academy of Engineering, who led a scientific team announced that a new‐type coronavirus, tentatively named by World Health Organization as the 2019‐new coronavirus (2019‐nCoV), had caused this outbreak. 1 The 2019‐nCoV has a different coronavirus‐specific nucleic acid sequence from known human coronavirus species, which are similar to some of the beta coronaviruses identified in bats. 2 , 3 The virus‐specific nucleic acid sequences were detected in lung fluid, blood and throat swab samples in 15 patients and the virus that was isolated showed a typical coronavirus appearance under electron microscopy. Further research will be conducted to better understand the new coronavirus to develop antiviral agents and vaccines. 4 We applauded the excellent job that has been done so far. The infection was first described in December. Within 9 days, a special team consisted of physicians, scientists and epidemiologists who ruled out several extremely contagious pathogens including SARS, which killed hundreds of people more than a decade ago, and MERS. This has surely alleviated environmental concerns as Hong Kong authorities had quickly stepped up the disinfection of trains and airplanes and checks of passengers due to this outbreak. Most of the patients visited the fish and wild animal market last month in Wuhan. This fish and wild animal market also sold live animals such as poultry, bats, marmots, and snakes. All patients received prompt supportive treatment in quarantine. Among them, seven patients were in serious condition and one patient died. All of the 42 patients so far confirmed were from China except one Thailand patient who was a traveler from Wuhan. Eight patients have been cured of the disease and were discharged from the hospital last week. The 2019‐nCoV now have been isolated from multiple patients and appears to be the culprit. But the mystery has not been completely solved yet. Until there is a formal published scientific manuscript, the facts can be argued, particularly regarding causality despite these facts having been officially announced. The data collected so far is not enough to confirm the causal relationship between the new‐type coronavirus and the respiratory disease based on classical Koch's postulates or modified ones as suggested by Fredricks and Relman. 5 The viral‐specific nucleic acids were only discovered in 15 patients, and successful virus culture was extremely limited to only a few patients. There remains considerable work to be done to differentiate between colonization, shedding, and infection. Additional strains of the 2019‐nCoV need to be isolated to study their homologies. It is expected that antigens and monoclonal antibodies will be developed so serology can be used to confirm previous and acute infection status. The episode demonstrates further the need for rapid and accurate detection and identification methods that can be used in the local hospitals and clinics bearing the burden of identifying and treating patients. Recently, the Clinical Laboratory Improvement Amendments (CLIA) of 1988 has waived highly sensitive and specific molecular devices known as CLIA‐waived devices so that these devices are gradually becoming available for point of care testing. Finally, the epidemiological similarity between this outbreak and that of SARS in 2002‐2003 6 is striking. SARS was then traced to animal markets 7 and eventually to palm civets. 8 Later bats were identified as animal reservoirs. 9 Could this novel coronavirus be originated from wild animals? The family Coronaviridae includes two subfamilies. 10 One, the subfamily Coronavirinae, contains a substantial number of pathogens of mammals that individually cause a remarkable variety of diseases, including pneumonia. In humans, coronaviruses are among the spectrum of viruses that cause the common cold as well as more severe respiratory disease—specifically SARS and MERS, which are both zoonoses. The second subfamily, Torovirinae, contains pathogens of both terrestrial and aquatic animals. The genus Torovirus includes the type species, equine torovirus (Berne virus), which was first isolated from a horse with diarrhea, and the Breda virus, which was first isolated from neonatal calves with diarrhea. White bream virus from fish is the type species of the genus Bafinivirus. However, there is no evidence so far that the seafood from the fish and animal market caused 2019‐nCoV‐associated pneumonia. This epidemiologic similarity clearly provides a starting point for the further investigation of this outbreak. In the meantime, this fish and animal market has been closed until the epidemiological work determines the animal host of this novel coronavirus. Only then will the miracle be complete.
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            Characterization of a novel coronavirus associated with severe acute respiratory syndrome.

            P Rota (2003)
            In March 2003, a novel coronavirus (SARS-CoV) was discovered in association with cases of severe acute respiratory syndrome (SARS). The sequence of the complete genome of SARS-CoV was determined, and the initial characterization of the viral genome is presented in this report. The genome of SARS-CoV is 29,727 nucleotides in length and has 11 open reading frames, and its genome organization is similar to that of other coronaviruses. Phylogenetic analyses and sequence comparisons showed that SARS-CoV is not closely related to any of the previously characterized coronaviruses.
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              Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

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                Author and article information

                Journal
                J Biomol Struct Dyn
                J. Biomol. Struct. Dyn
                Journal of Biomolecular Structure & Dynamics
                Taylor & Francis
                0739-1102
                1538-0254
                13 July 2020
                2020
                : 1-11
                Affiliations
                Núcleo Colaborativo de Biosistemas, Universidade Federal de Jataí , Jataí, GO, Brazil
                Author notes

                Supplemental data for this article can be accessed online at https://doi.org/10.1080/07391102.2020.1792992.

                CONTACT Roosevelt Alves da Silva rooseveltfisicaufg@ 123456gmail.com Núcleo Colaborativo de Biosistemas, Universidade Federal de Goiás , Jataí, GO75801-615, Brazil.
                Author information
                https://orcid.org/0000-0002-8944-8148
                https://orcid.org/0000-0001-5624-4790
                Article
                1792992
                10.1080/07391102.2020.1792992
                7443570
                32657643
                64eec53c-03cd-43b1-9b3b-6b6c576a43df
                © 2020 Informa UK Limited, trading as Taylor & Francis Group

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                Page count
                Figures: 6, Tables: 2, Pages: 11, Words: 5850
                Categories
                Research Article
                Research Article

                sars-cov-2,non-structural protein 1,molecular dynamics simulation,drug design,computational biology,molecular modeling,virtual screening

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