DockCoV2: a drug database against SARS-CoV-2

Abstract The current state of the COVID-19 pandemic is a global health crisis. To fight the novel coronavirus, one of the best-known ways is to block enzymes essential for virus replication. Currently, we know that the SARS-CoV-2 virus encodes about 29 proteins such as spike protein, 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), Papain-like protease (PLpro), and nucleocapsid (N) protein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) for viral entry and transmembrane serine protease family member II (TMPRSS2) for spike protein priming. Thus in order to speed up the discovery of potential drugs, we develop DockCoV2, a drug database for SARS-CoV-2. DockCoV2 focuses on predicting the binding affinity of FDA-approved and Taiwan National Health Insurance (NHI) drugs with the seven proteins mentioned above. This database contains a total of 3,109 drugs. DockCoV2 is easy to use and search against, is well cross-linked to external databases, and provides the state-of-the-art prediction results in one site. Users can download their drug-protein docking data of interest and examine additional drug-related information on DockCoV2. Furthermore, DockCoV2 provides experimental information to help users understand which drugs have already been reported to be effective against MERS or SARS-CoV. DockCoV2 is available at https://covirus.cc/drugs/.

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Molecular Mechanism of Evolution and Human Infection with SARS-CoV-2

Viruses ◽

10.3390/v12040428 ◽

2020 ◽

Vol 12 (4) ◽

pp. 428 ◽

Cited By ~ 41

Author(s):

Jiahua He ◽

Huanyu Tao ◽

Yumeng Yan ◽

Sheng-You Huang ◽

Yi Xiao

Keyword(s):

Molecular Mechanisms ◽

Vaccine Development ◽

Md Simulations ◽

Protein Docking ◽

Human Infection ◽

Spike Protein ◽

Temperature Sensitive ◽

Health Crisis ◽

Novel Coronavirus ◽

Respiratory Coronavirus

The outbreak of a novel coronavirus, which was later formally named the severe acute respiratory coronavirus 2 (SARS-CoV-2), has caused a worldwide public health crisis. Previous studies showed that SARS-CoV-2 is highly homologous to SARS-CoV and infects humans through the binding of the spike protein to ACE2. Here, we have systematically studied the molecular mechanisms of human infection with SARS-CoV-2 and SARS-CoV by protein-protein docking and MD simulations. It was found that SARS-CoV-2 binds ACE2 with a higher affinity than SARS-CoV, which may partly explain that SARS-CoV-2 is much more infectious than SARS-CoV. In addition, the spike protein of SARS-CoV-2 has a significantly lower free energy than that of SARS-CoV, suggesting that SARS-CoV-2 is more stable and may survive a higher temperature than SARS-CoV. This provides insights into the evolution of SARS-CoV-2 because SARS-like coronaviruses have originated in bats. Our computation also suggested that the RBD-ACE2 binding for SARS-CoV-2 is much more temperature-sensitive than that for SARS-CoV. Thus, it is expected that SARS-CoV-2 would decrease its infection ability much faster than SARS-CoV when the temperature rises. These findings would be beneficial for the disease prevention and drug/vaccine development of SARS-CoV-2.

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SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients

Frontiers in Neurology ◽

10.3389/fneur.2020.587384 ◽

2020 ◽

Vol 11 ◽

Author(s):

Dimitris G. Placantonakis ◽

Maria Aguero-Rosenfeld ◽

Abdallah Flaifel ◽

John Colavito ◽

Kenneth Inglima ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Viral Entry ◽

Cell Types ◽

Host Cells ◽

Nasopharyngeal Swab ◽

Rt Pcr ◽

Neurologic Sequelae ◽

Show Evidence ◽

Novel Coronavirus ◽

Transmembrane Serine Protease

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.

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Jeopardy of COVID-19: Rechecking the Perks of Phytotherapeutic Interventions

Molecules ◽

10.3390/molecules26226783 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6783

Author(s):

Priyanka Saha ◽

Subhankar Bose ◽

Amit Kumar Srivastava ◽

Anis Ahmad Chaudhary ◽

Rajiv Lall ◽

...

Keyword(s):

Medicinal Plants ◽

Clinical Status ◽

Active Metabolites ◽

Health Crisis ◽

Chemical Structures ◽

Clinical Complications ◽

Acute Kidney Disease ◽

Antiviral Activities ◽

Novel Coronavirus ◽

Transmembrane Serine Protease

The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19.

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COVID-19 and Extracellular Vesicles: An Intriguing Interplay

Kidney & Blood Pressure Research ◽

10.1159/000511402 ◽

2020 ◽

Vol 45 (5) ◽

pp. 661-670

Author(s):

Gabriella Pocsfalvi ◽

Ramila Mammadova ◽

Ana Paulina Ramos Juarez ◽

Ramesh Bokka ◽

Francesco Trepiccione ◽

...

Keyword(s):

Extracellular Vesicles ◽

Viral Entry ◽

Viral Infections ◽

Vaccine Development ◽

Antiviral Drug ◽

The Novel ◽

Health Crisis ◽

Cargo Delivery ◽

The Many ◽

Novel Coronavirus

Background: The outbreak of severe acute respiratory syndrome β-coronavirus 2 (SARS-CoV-2) has the potential to become a long-lasting global health crisis. The number of people infected with the novel coronavirus has surpassed 22 million globally, resulting in over 700,000 deaths with more than 15 million people having recovered (https://covid19.who.int). Enormous efforts are underway for rapid vaccine and treatment developments. Amongst the many ways of tackling the novel coronavirus disease 2019 (COVID-19) pandemic, extracellular vesicles (EVs) are emerging. Summary: EVs are lipid bilayer-enclosed structures secreted from all types of cells, including those lining the respiratory tract. They have established roles in lung immunity and are involved in the pathogenesis of various lung diseases, including viral infection. In this review, we point out the roles and possible contribution of EVs in viral infections, as well as ongoing EV-based approaches for the treatment of COVID-19, including clinical trials. Key Messages: EVs share structural similarities to viruses and recent findings demonstrate that viruses exploit EVs for cellular exit and EVs exploit viral entry mechanisms for cargo delivery. Moreover, EV-virus interplay could be exploited for future antiviral drug and vaccine development. EV-based therapies, especially the mesenchymal stem cell-derived EVs, are being intensively studied for the treatment of COVID-19.

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Increased susceptibility of human endothelial cells to infections by SARS-CoV-2 variants

Basic Research in Cardiology ◽

10.1007/s00395-021-00882-8 ◽

2021 ◽

Vol 116 (1) ◽

Cited By ~ 1

Author(s):

Julian U. G. Wagner ◽

Denisa Bojkova ◽

Mariana Shumliakivska ◽

Guillermo Luxán ◽

Luka Nicin ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Dysfunction ◽

Umbilical Vein ◽

Cell Number ◽

Spike Protein ◽

Human Endothelial Cells ◽

Health Crisis ◽

Novel Coronavirus ◽

Umbilical Vein Endothelial Cells

AbstractCoronavirus disease 2019 (COVID-19) spawned a global health crisis in late 2019 and is caused by the novel coronavirus SARS-CoV-2. SARS-CoV-2 infection can lead to elevated markers of endothelial dysfunction associated with higher risk of mortality. It is unclear whether endothelial dysfunction is caused by direct infection of endothelial cells or is mainly secondary to inflammation. Here, we investigate whether different types of endothelial cells are susceptible to SARS-CoV-2. Human endothelial cells from different vascular beds including umbilical vein endothelial cells, coronary artery endothelial cells (HCAEC), cardiac and lung microvascular endothelial cells, or pulmonary arterial cells were inoculated in vitro with SARS-CoV-2. Viral spike protein was only detected in HCAECs after SARS-CoV-2 infection but not in the other endothelial cells tested. Consistently, only HCAEC expressed the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), required for virus infection. Infection with the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.2 resulted in significantly higher levels of viral spike protein. Despite this, no intracellular double-stranded viral RNA was detected and the supernatant did not contain infectious virus. Analysis of the cellular distribution of the spike protein revealed that it co-localized with endosomal calnexin. SARS-CoV-2 infection did induce the ER stress gene EDEM1, which is responsible for clearance of misfolded proteins from the ER. Whereas the wild type of SARS-CoV-2 did not induce cytotoxic or pro-inflammatory effects, the variant B.1.1.7 reduced the HCAEC cell number. Of the different tested endothelial cells, HCAECs showed highest viral uptake but did not promote virus replication. Effects on cell number were only observed after infection with the variant B.1.1.7, suggesting that endothelial protection may be particularly important in patients infected with this variant.

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TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein

Viruses ◽

10.3390/v13030384 ◽

2021 ◽

Vol 13 (3) ◽

pp. 384

Author(s):

Mai Kishimoto ◽

Kentaro Uemura ◽

Takao Sanaki ◽

Akihiko Sato ◽

William W. Hall ◽

...

Keyword(s):

Viral Entry ◽

Vaccine Development ◽

Spike Protein ◽

Tissue Tropism ◽

Type Ii ◽

Angiotensin Converting Enzyme 2 ◽

Exogenous Expression ◽

Transmembrane Serine Protease ◽

The Impact

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) utilizes host proteases, including a plasma membrane-associated transmembrane protease, serine 2 (TMPRSS2) to cleave and activate the virus spike protein to facilitate cellular entry. Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.

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Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells

10.26434/chemrxiv.12009582.v1 ◽

2020 ◽

Cited By ~ 5

Author(s):

Stefano Rensi ◽

Russ B Altman ◽

Tianyun Liu ◽

Yu-Chen Lo ◽

Greg McInnes ◽

...

Keyword(s):

Serine Protease ◽

Treatment Options ◽

Clinical Effects ◽

The Novel ◽

Clinical Tool ◽

Binding Score ◽

Serine Protease Family ◽

Novel Coronavirus ◽

Transmembrane Serine Protease ◽

High Binding Affinity

The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects. Nonetheless, if these compounds significantly inhibit SARS-CoV-2 infection, they could represent a potentially useful clinical tool.

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Structural analysis of COVID-19 spike protein in recognizing the ACE2 receptor of different mammalian species and its susceptibility to viral infection.

10.21203/rs.3.rs-98738/v1 ◽

2020 ◽

Author(s):

Tirthankar Koley ◽

Shivani Madaan ◽

Sanghati Roy Chowdhury ◽

Manoj Kumar ◽

Punit Kaur ◽

...

Keyword(s):

Hydrophobic Interactions ◽

Interaction Analysis ◽

Mammalian Species ◽

Protein Docking ◽

Glycosylation Site ◽

Spike Protein ◽

Amino Acid Residues ◽

New Public Health ◽

Potential Mode ◽

Novel Coronavirus

Abstract The pandemic COVID-19 caused by a novel coronavirus SARS-CoV-2 spread worldwide as a new public health emergency. The SARS-CoV-2 infects humans by binding to glycosylated ACE2 receptor present in the inner lining of the lungs, heart, intestine and kidney. The COVID spike 2 protein recognizes the ACE2 receptor at the N-terminal helices of the metalloprotease domain. The residues Gln24, Thr27, Lys31, His34, Glu37, Asp38, Tyr41, Gln42 from helix α1; Leu79, Met82, Tyr83 from helix α2 and Gln325, Glu329, Asn330, Lys353 from loop connecting β4 and β5 strands form a concave surface surrounded by four glycosylation sites Asn53, Asn90, Asn103 and Asn322 form interactions with the spike protein. However, no significant data on the susceptibility of animals for infection or transmission. Therefore, we performed the comparative protein-protein docking analysis using the crystal structure of spike protein and homology models of the ACE2 receptor from 16 commonly found mammalian species to understand the potential mode of spike binding. Our comprehensive sequence and structure-based interaction analysis revealed the natural substitution of amino acid residues Gln24, His34, Phe40 and Met82 in the N-terminal α1 and α2 helices results in loss of crucial network of hydrogen-bonded and hydrophobic interactions with spike 2 RBD domain. Besides, the absence of N-linked glycosylation site Asn103 in other mammals further reduces the binding affinity between spike and ACE2 receptor. Hence, these changes explain the differences in the susceptibility and host pathogenesis in other mammalian species.

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The sequence at Spike S1/S2 site enables cleavage by furin and phospho-regulation in SARS-CoV2 but not in SARS-CoV1 or MERS-CoV

Scientific Reports ◽

10.1038/s41598-020-74101-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Mihkel Örd ◽

Ilona Faustova ◽

Mart Loog

Keyword(s):

Viral Entry ◽

Spike Protein ◽

Target Cells ◽

The Novel ◽

Novel Coronavirus ◽

Cleavage Motif ◽

Left Middle ◽

Surprising Finding

Abstract The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680SPRRAR↓SV687 forming a cleavage motif RxxR for furin-like enzymes at the boundary of S1/S2 subunits. Cleavage at S1/S2 is important for efficient viral entry into target cells. The insertion is absent in other CoV-s of the same clade, including SARS-CoV1 that caused the 2003 outbreak. However, an analogous cleavage motif was present at S1/S2 of the Spike protein of the more distant Middle East Respiratory Syndrome coronavirus MERS-CoV. We show that a crucial third arginine at the left middle position, comprising a motif RRxR is required for furin recognition in vitro, while the general motif RxxR in common with MERS-CoV is not sufficient for cleavage. Further, we describe a surprising finding that the two serines at the edges of the insert SPRRAR↓SV can be efficiently phosphorylated by proline-directed and basophilic protein kinases. Both phosphorylations switch off furin’s ability to cleave the site. Although phospho-regulation of secreted proteins is still poorly understood, further studies, supported by a recent report of ten in vivo phosphorylated sites in the Spike protein of SARS-CoV2, could potentially uncover important novel regulatory mechanisms for SARS-CoV2.

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Analysis of SARS-CoV-2 Spike Protein as The Key Target in the Development of Antiviral Candidates for COVID-19 through Computational Study

Journal Of Tropical Pharmacy And Chemistry ◽

10.25026/jtpc.v5i4.254 ◽

2021 ◽

Vol 5 (4) ◽

pp. 347-352

Author(s):

Taufik Muhammad Fakih ◽

Mentari Luthfika Dewi

Keyword(s):

Binding Sites ◽

Computational Study ◽

Docking Simulation ◽

Competitive Inhibitor ◽

Protein Docking ◽

Spike Protein ◽

Health Crisis ◽

Angiotensin Converting Enzyme 2 ◽

Public Health Crisis ◽

Spike Proteins

The recent public health crisis is threatening the world with the emergence of the spread of the new coronavirus 2019 (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus originates from bats and is transmitted to humans through unknown intermediate animals in Wuhan, China in December 2019. Advances in technology have opened opportunities to find candidates for natural compounds capable of preventing and controlling COVID-19 infection through inhibition of spike proteins of SARS-CoV-2. This research aims to identify, evaluate, and explore the structure of spike protein macromolecules from three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) and their effects on Angiotensin-Converting Enzyme 2 (ACE-2) using computational studies. Based on the identification of the three spike protein macromolecules, it was found that there was a similarity between the active binding sites of ACE-2. These observations were then confirmed using a protein-docking simulation to observe the interaction of the protein spike to the active site of ACE-2. SARS-COV-2 spike protein has the strongest bond to ACE-2, with an ACE score of −1341.85 kJ/mol. Therefore, some of this information from the results of this research can be used as a reference in the development of competitive inhibitor candidates for SARS-CoV-2 spike proteins for the treatment of COVID-19 infectious diseases.

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