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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP5 (412)

ProteinS (63)

NSP3 (57)

ComplexRdRp (51)

ProteinN (11)


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SARS-CoV-2 Proteins
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    Structure-based drug design, virtual screening and high-throughput screening rapidly identify antiviral leads targeting COVID-19 MESHD

    Authors: Zhenming Jin; Xiaoyu Du; Yechun Xu; Yongqiang Deng; Meiqin Liu; Yao Zhao; Bing Zhang; Xiaofeng Li; Leike Zhang; Chao Peng; Yinkai Duan; Jing Yu; Lin Wang; Kailin Yang; Fengjiang Liu; Rendi Jiang; Xinglou Yang; Tian You; Xiaoce Liu; Xiuna Yang; Fang Bai; Hong Liu; Xiang Liu; Luke W. Guddat; Wenqing Xu; Gengfu Xiao; Chengfeng Qin; Zhengli Shi; Hualiang Jiang; Zihe Rao; Haitao Yang

    doi:10.1101/2020.02.26.964882 Date: 2020-02-27 Source: bioRxiv

    A new coronavirus (CoV) identified as COVID-19 MESHD virus is the etiological agent responsible for the 2019-2020 viral pneumonia MESHD outbreak that commenced in Wuhan1-4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 MESHD virus main protease PROTEIN ( Mpro PROTEIN). Mpro PROTEIN is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 MESHD virus Mpro PROTEIN in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro PROTEIN. Six of these inhibit Mpro PROTEIN with IC50 values ranging from 0.67 to 21.4 M. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.

    Pharmacoinformatics and Molecular Dynamic Simulation Studies Reveal Potential Inhibitors of SARS-CoV-2 Main Protease PROTEIN 3CLpro PROTEIN

    Authors: Mubarak A. Alamri; Muhammad Tahir ul Qamar; Safar M. Alqahtani

    id:10.20944/preprints202002.0308.v1 Date: 2020-02-23 Source: Preprints.org

    The SARS-CoV-2 was confirmed to cause the regional outbreak of coronavirus disease 2019 MESHD ( COVID-19 MESHD) in Wuhan, China. The 3C-like protease ( 3CLpro PROTEIN), an essential enzyme for viral replication, is a valid target to compacts SARS-CoV MESHD and MERS-CoV. In this research, an integrated library consisting of 1000 compounds from Asinex Focused Covalent (AFCL) library and 16 FDA-approved protease inhibitors were screened against SARS-CoV-2 3CLpro PROTEIN. Top compounds with significant docking scores and making stable interactions with catalytic dyad residues were obtained. The screening results in identification of compound 621 from AFCL library as well as Paritaprevir and Simeprevir from FDA-approved protease inhibitors as potential inhibitors of SARS-CoV-2 3CLpro PROTEIN. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro PROTEIN were characterized using 50 nanoseconds (ns) molecular dynamic (MD) simulation approach. The identified compounds are potential inhibitors worthy of further development as SARS-CoV-2 3CLpro PROTEIN inhibitors/drugs. Importantly, the identified FDA-approved therapeutics could be ready for clinical trials to treat infected MESHD patients and help to curb the COVID-19 MESHD.

    Inhibition of the Main Protease PROTEIN 3CL-pro of the Coronavirus Disease 19 via Structure-Based Ligand Design and Molecular Modeling

    Authors: Marina Macchiagodena; Marco Pagliai; Piero Procacci

    id:2002.09937v2 Date: 2020-02-23 Source: arXiv

    We have applied a computational strategy, based on the synergy of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease PROTEIN 3CL-pro of the SARS-Cov2 Coronavirus. Based on the recently resolved 6LU7 PDB structure, ligands were generated using a multimodal structure-based design and then optimally docked to the 6LU7 monomer. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV MESHD and SARS-CoV2 main proteases PROTEIN, irrespectively of the protonation state of the catalytic CYS-HIS dyad. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement. Molecular dynamics calculations fully confirm the stability in the 3CL-pro binding pocket of the most potent binder identified by docking, namely a chlorophenyl-pyridyl-carboxamide derivative.

    X-ray Structure of Main Protease PROTEIN of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

    Authors: Linlin Zhang; Daizong Lin; Xinyuanyuan Sun; Katharina Rox; Rolf Hilgenfeld

    doi:10.1101/2020.02.17.952879 Date: 2020-02-20 Source: bioRxiv

    A novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia MESHD originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease PROTEIN ( Mpro PROTEIN, also called 3CLpro PROTEIN) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro PROTEIN at 1.75 [A] resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-[A] crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.

    Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease PROTEIN by Deep Docking of 1.3 Billion Compounds

    Authors: Anh-Tien Ton; Francesco Gentile; Michael Hsing; Fuqiang Ban; Artem Cherkasov

    doi:10.26434/chemrxiv.11860077.v1 Date: 2020-02-19 Source: ChemRxiv

    The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 MESHD disease cause serious or even fatal respiratory tract infection MESHD and yet no FDA-approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel vaccine or a small molecule therapeutics for SARS-CoV-2. Along these efforts, the structure of SARS-CoV-2 main protease PROTEIN ( Mpro PROTEIN) has been rapidly resolved and made publicly available to facilitate global efforts to develop novel drug candidates.In recent month, our group has developed a novel deep learning platform – Deep Docking (DD) which enables very fast docking of billions of molecular structures and provides up to 6,000X enrichment on the top-predicted ligands compared to conventional docking workflow (without notable loss of information on potential hits). In the current work we applied DD to entire 1.3 billion compounds from ZINC15 library to identify top 1,000 potential ligands for SARS-CoV-2 Mpro PROTEIN. The compounds are made publicly available for further characterization and development by scientific community.

    Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like Protease ( 3CLpro PROTEIN) Structure: Virtual Screening Reveals Velpatasvir, Ledipasvir, and Other Drug Repurposing Candidates

    Authors: Yu Wai Chen; Chin-Pang Yiu; Kwok-Yin Wong

    doi:10.26434/chemrxiv.11831103.v2 Date: 2020-02-17 Source: ChemRxiv

    We prepared the three-dimensional model of the 2019-nCoV 3C-like protease ( 3CLpro PROTEIN) using the crystal structure of the highly-similar (96% identity) ortholog from the SARS-CoV MESHD. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are in the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV MESHD enzyme can be conferred on its 2019-nCoV counterpart. With the 3CLpro PROTEIN molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the 2019-nCoV with minimal side effects, commonly fatigue MESHD and headache MESHD. The drugs Epclusa (velpatasvir / sofosbuvir) and Harvoni (ledipasvir / sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.

    Potentially highly potent drugs for 2019-nCoV

    Authors: Duc Nguyen; Kaifu Gao; Jiahui Chen; Rui Wang; Guewei Wei

    doi:10.1101/2020.02.05.936013 Date: 2020-02-13 Source: bioRxiv

    The World Health Organization (WHO) has declared the 2019 novel coronavirus (2019-nCoV) infection outbreak a global health emergency. Currently, there is no effective anti-2019-nCoV medication. The sequence identity of the 3CL proteases PROTEIN of 2019-nCoV and SARS is 96%, which provides a sound foundation for structural-based drug repositioning (SBDR). Based on a SARS 3CL protease PROTEIN X-ray crystal structure, we construct a 3D homology structure of 2019-nCoV 3CL protease PROTEIN. Based on this structure and existing experimental datasets for SARS 3CL protease PROTEIN inhibitors, we develop an SBDR model based on machine learning and mathematics to screen 1465 drugs in the DrugBank that have been approved by the U.S. Food and Drug Administration (FDA). We found that many FDA approved drugs are potentially highly potent to 2019-nCoV.

    Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication

    Authors: Linlin Zhang; Daizong Lin; Yuri Kusov; Yong Nian; Qingjun Ma; Jiang Wang; Albrecht von Brunn; Pieter Leyssen; Kristina Lanko; Johan Neyts; Adriaan de Wilde; Eric J. Snijder; Hong Liu; Rolf Hilgenfeld

    doi:10.1101/2020.02.10.936898 Date: 2020-02-10 Source: bioRxiv

    The main protease PROTEIN of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued structure-based design of peptidomimetic -ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease:inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected MESHD cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the -ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against Middle East Respiratory Syndrome coronavirus MESHD.

    Therapeutic Drugs Targeting 2019-nCoV Main Protease PROTEIN by High-Throughput Screening

    Authors: Yan Li; Jinyong Zhang; Ning Wang; Haibo Li; Yun Shi; Gang Guo; Kaiyun Liu; Hao Zeng; Quanming Zou

    doi:10.1101/2020.01.28.922922 Date: 2020-01-29 Source: bioRxiv

    2019 Novel Coronavirus (2019-nCoV) is a virus identified as the cause of the outbreak of pneumonia MESHD first detected in Wuhan, China. Investigations on the transmissibility, severity, and other features associated with this virus are ongoing. Currently, there is no vaccine or therapeutic antibody to prevent the infection, and more time is required to develop an effective immune strategy against the pathogen. In contrast, specific inhibitors targeting the key protease involved in replication and proliferation of the virus are the most effective means to alleviate the epidemic. The main protease PROTEIN of SARS-CoV MESHD is essential for the life cycle of the virus, which showed 96.1% of similarity with the main proteaseof 2019-nCoV, is considered to be an attractive target for drug development. In this study, we have identified 4 small molecular drugs with high binding capacity with SARS-CoV MESHD main protease PROTEIN by high-throughput screening based on the 8,000 clinical drug libraries, all these drugs have been widely used in clinical applications with guaranteed safety, which may serve as promising candidates to treat the infection of 2019-nCoV.

    Potential inhibitors for 2019-nCoV coronavirus M protease from clinically approved medicines

    Authors: Xin Liu; Xiu-Jie Wang

    doi:10.1101/2020.01.29.924100 Date: 2020-01-29 Source: bioRxiv

    Starting from December 2019, a novel coronavirus, named 2019-nCoV, was found to cause Severe Acute Respiratory ( SARI HGNC) symptoms and rapid pandemic in China. With the hope to identify candidate drugs for 2019-nCoV, we adopted a computational approach to screen for available commercial medicines which may function as inhibitors for the Mpro PROTEIN of 2019-nCoV. Up to 10 commercial medicines that may form hydrogen bounds to key residues within the binding pocket of 2019-nCoV Mpro PROTEIN were identified, which may have higher mutation tolerance than lopinavir/ritonavir and may also function as inhibitors for other coronaviruses with similar Mpro PROTEIN binding sites and pocket structures.

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MeSH Disease
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SARS-CoV-2 Proteins


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