Virtual screening and molecular dynamics simulation for identification of natural antiviral agents targeting SARS-CoV-2 NSP10.

New variations of SARS-CoV-2 continue to emerge in the global pandemic, which may be resistant to at least some vaccines in COVID-19, indicating that drug and vaccine development must be continuously strengthened. NSP10 plays an essential role in SARS-CoV-2 viral life cycle. It stimulates the enzymatic activities of NSP14-ExoN and NSP16-O-MTase by the formation of NSP10/NSP14 and NSP10/NSP16 complexes. Inhibiting NSP10 can block the binding of NSP10 to NSP14 and NSP16. This study has identified potential natural NSP10 inhibitors from ZINC database. The protein druggable pocket was identified for screening candidates. Molecular docking of the selected compounds was performed and MM-GBSA binding energy was calculated. After ADMET assessment, 4 hits were obtained for favorable druggability. The analysis of site interactions suggested that the hits all had excellent binding. Molecular dynamics studies revealed that selected natural compounds stably bind to NSP10. These compounds were identified as potential leads against NSP10 for the development of strategies to combat SARS-CoV-2 replication and could serve as the basis for further studies.

A Large-Scale Clinical Validation Study Using nCapp Cloud Plus Terminal by Frontline Doctors for the Rapid Diagnosis of COVID-19 and COVID-19 pneumonia in China

Background The outbreak of coronavirus disease 2019 (COVID-19) has become a global pandemic acute infectious disease, especially with the features of possible asymptomatic carriers and high contagiousness. Currently, it is difficult to quickly identify asymptomatic cases or COVID-19 patients with pneumonia due to limited access to reverse transcription-polymerase chain reaction (RT-PCR) nucleic acid tests and CT scans. Goal This study aimed to develop a scientific and rigorous clinical diagnostic tool for the rapid prediction of COVID-19 cases based on a COVID-19 clinical case database in China, and to assist doctors to efficiently and precisely diagnose asymptomatic COVID-19 patients and cases who had a false-negative RT-PCR test result. Methods With online consent, and the approval of the ethics committee of Zhongshan Hospital Fudan University (NCT04275947, B2020-032R) to ensure that patient privacy is protected, clinical information has been uploaded in real-time through the New Coronavirus Intelligent Auto-diagnostic Assistant Application of cloud plus terminal (nCapp) by doctors from different cities (Wuhan, Shanghai, Harbin, Dalian, Wuxi, Qingdao, Rizhao, and Bengbu) during the COVID-19 outbreak in China. By quality control and data anonymization on the platform, a total of 3,249 cases from COVID-19 high-risk groups were collected. The effects of different diagnostic factors were ranked based on the results from a single factor analysis, with 0.05 as the significance level for factor inclusion and 0.1 as the significance level for factor exclusion. Independent variables were selected by the step-forward multivariate logistic regression analysis to obtain the probability model. Findings We applied the statistical method of a multivariate regression model to the training dataset (1,624 cases) and developed a prediction model for COVID-19 with 9 clinical indicators that are accessible. The area under the receiver operating characteristic (ROC) curve (AUC) for the model was 0.88 (95% CI: 0.86, 0.89) in the training dataset and 0.84 (95% CI: 0.82, 0.86) in the validation dataset (1,625 cases). Discussion With the assistance of nCapp, a mobile-based diagnostic tool developed from a large database that we collected from COVID-19 high-risk groups in China, frontline doctors can rapidly identify asymptomatic patients and avoid misdiagnoses of cases with false-negative RT-PCR results.

Design of SARS-CoV-2 Mpro, PLpro dual-target inhibitors based on deep reinforcement learning and virtual screening.

Background: Since December 2019, SARS-CoV-2 has continued to spread rapidly around the world. The effective drugs may provide a long-term strategy to combat this virus. The main protease (Mpro) and papain-like protease (PLpro) are two important targets for the inhibition of SARS-CoV-2 virus replication and proliferation. Materials & methods: In this study, deep reinforcement learning, covalent docking and molecular dynamics simulations were used to identify novel compounds that have the potential to inhibit both Mpro and PLpro. Results & conclusion: Three compounds were identified that can effectively occupy the Mpro protein cavity with the PLpro protein cavity and form high-frequency contacts with key amino acid residues (Mpro: His41, Cys145, Glu166; PLpro: Cys111). These three compounds can be further investigated as potential lead compounds for SARS-CoV-2 inhibitors.

Chinese experts’ consensus on the Internet of Things-aided diagnosis and treatment of coronavirus disease 2019 (COVID-19)

The aim is to diagnose COVID-19 earlier and to improve its treatment by applying medical technology, the “COVID-19 Intelligent Diagnosis and Treatment Assistant Program (nCapp)” based on the Internet of Things. Terminal eight functions can be implemented in real-time online communication with the “cloud” through the page selection key. According to existing data, questionnaires, and check results, the diagnosis is automatically generated as confirmed, suspected, or suspicious of 2019 novel coronavirus (2019-nCoV) infection. It classifies patients into mild, moderate, severe or critical pneumonia. nCapp can also establish an online COVID-19 real-time update database, and it updates the model of diagnosis in real time based on the latest real-world case data to improve diagnostic accuracy. Additionally, nCapp can guide treatment. Front-line physicians, experts, and managers are linked to perform consultation and prevention. nCapp also contributes to the long-term follow-up of patients with COVID-19. The ultimate goal is to enable different levels of COVID-19 diagnosis and treatment among different doctors from different hospitals to upgrade to the national and international through the intelligent assistance of the nCapp system. In this way, we can block disease transmission, avoid physician infection, and epidemic prevention and control as soon as possible.