scholarly journals Designing Inhibitors for the SARS CoV Main Protease as Anti-SARS Drugs

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Hamza Bari ◽  
Arif Ali Awan
Keyword(s):  
Substrate Binding ◽  
Rapid Development ◽  
Respiratory Illness ◽  
Significant Inhibition ◽  
Computational Techniques ◽  
Chemical Structures ◽  
Main Protease ◽  
Binding Cavity ◽  
Antiviral Chemotherapy ◽  
Novel Coronavirus

Severe Acute Respiratory Syndrome (SARS) is a serious respiratory illness reported in parts of Asia and Canada. A novel coronavirus (CoV) has been isolated and identified as the cause of the SARS for which there is currently no effective treatment. Given the epidemic, the rapid development of efficacious antiviral drugs is needed. The key replicative enzyme SARS CoV main protease (Mpro) represents an attractive target for antiviral chemotherapy. Detailed structural study of the substrate binding cavity led to the generation of a 3-D pharmacophore. Subsets of chemical structures were extracted from the commercial databases by using the defined pharmacophore. Compound mapping to the pharmacophore were docked into the substrate-binding cavity and scored. The selected chemicals were assayed against the SARS CoV Mpro for their inhibitory activity. Three of the compounds showed significant inhibition of the SARS CoV Mpro at low micromolar concentration. This study provides potential lead compounds for specific SARS CoV protease inhibitors. It also signifies the utility of computational techniques for rapid discovery of inhibitors for novel targets.

scholarly journals Structure-Based Virtual Screening of a Natural Product Database to Identify Several Possible SARS-CoV-2 Main Protease Inhibitors

2020 ◽  
Author(s):  
Azhagiya Singam Ettayapuram Ramaprasad ◽  
Michele La merrill ◽  
Kathleen A. Durkin ◽  
Martyn T. Smith
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Respiratory Illness ◽  
Dynamics Simulation ◽  
Effective Vaccine ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Seriously Ill Patients ◽  
Enormous Number ◽  
Seriously Ill

<p>A novel coronavirus (SARS-CoV-2) has been the cause of a recent pandemic of respiratory illness known as COVID-19. The lack of anti-viral drugs or vaccines to control the infection has resulted in an enormous number of seriously ill patients requiring hospitalization. In the absence of an effective vaccine, there is an urgent need for therapies which can fight COVID-19 infection. Readily available compounds in foods and plants may be one source of anti-viral compounds. Here, natural product chemicals from the Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products Database (NuBBE<sub>DB</sub>) were screened against the main protease (Mpro) of SARS-CoV-2. This protease was chosen as a target due to its importance in the replication of SARS-CoV-2. Molecular docking was used to screen the natural products against Mpro to identify potential candidates. The identified candidates were further filtered using molecular dynamics simulation investigation. Nine natural compounds were identified for experimental validation, with carlinoside and quercetin 3-o-sophoroside being the top candidates. </p>

scholarly journals Substrate specificity profiling of SARS-CoV-2 main protease enables design of activity-based probes for patient-sample imaging

2020 ◽  
Author(s):  
Wioletta Rut ◽  
Katarzyna Groborz ◽  
Linlin Zhang ◽  
Xinyuanyuan Sun ◽  
Mikolaj Zmudzinski ◽  
...  
Keyword(s):  
Unnatural Amino Acids ◽  
Drug Targets ◽  
Rapid Development ◽  
Antiviral Treatment ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
International Travel ◽  
Substrate Preferences ◽  
Main Protease ◽  
Novel Coronavirus

AbstractIn December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective antiviral treatment for coronavirus disease 2019 (COVID-19); therefore, research efforts are focused on the rapid development of vaccines and antiviral drugs. The SARS-CoV-2 main protease constitutes one of the most attractive antiviral drug targets. To address this emerging problem, we have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases, using natural and a large panel of unnatural amino acids. On the basis of these findings, we designed and synthesized an inhibitor and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. Using this approach we visualized SARS-CoV-2 active Mpro within nasopharyngeal epithelial cells of a patient with active COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents or diagnostic tests.

scholarly journals Structure-Based Virtual Screening of a Natural Product Database to Identify Several Possible SARS-CoV-2 Main Protease Inhibitors

2020 ◽  
Author(s):  
Azhagiya Singam Ettayapuram Ramaprasad ◽  
Michele La merrill ◽  
Kathleen A. Durkin ◽  
Martyn T. Smith
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Respiratory Illness ◽  
Dynamics Simulation ◽  
Effective Vaccine ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Seriously Ill Patients ◽  
Enormous Number ◽  
Seriously Ill

<p>A novel coronavirus (SARS-CoV-2) has been the cause of a recent pandemic of respiratory illness known as COVID-19. The lack of anti-viral drugs or vaccines to control the infection has resulted in an enormous number of seriously ill patients requiring hospitalization. In the absence of an effective vaccine, there is an urgent need for therapies which can fight COVID-19 infection. Readily available compounds in foods and plants may be one source of anti-viral compounds. Here, natural product chemicals from the Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products Database (NuBBE<sub>DB</sub>) were screened against the main protease (Mpro) of SARS-CoV-2. This protease was chosen as a target due to its importance in the replication of SARS-CoV-2. Molecular docking was used to screen the natural products against Mpro to identify potential candidates. The identified candidates were further filtered using molecular dynamics simulation investigation. Nine natural compounds were identified for experimental validation, with carlinoside and quercetin 3-o-sophoroside being the top candidates. </p>

scholarly journals Identification of potential inhibitors of coronavirus SARS-CoV-2 using the methods of virtual screening and molecular modeling

2020 ◽  
Vol 64 (3) ◽  
pp. 308-316
Author(s):  
A. M. Andrianov ◽  
Yu. V. Kornoushenko ◽  
A. D. Karpenko ◽  
A. V. Tuzikov
Keyword(s):  
Molecular Modeling ◽  
Virtual Screening ◽  
Etiologic Agent ◽  
The Novel ◽  
Chemical Structures ◽  
Main Protease ◽  
Structural And Functional Properties ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Effective Drugs

To find small-molecule compounds that can simulate the structural and functional properties of the high affinity X77 ligand of the main protease of SARS-CoV-2 - etiologic agent of COVID-19, the virtual screening of 9 molecular libraries of the Pharmit web server containing over 213.5 million chemical structures was performed. Using molecular modeling, the neutralizing activity of the identified molecules was evaluated, resulting in 5 leader compounds promising for synthesis and testing for antiviral activity. The data obtained indicate that these compounds may be used as basic structures for the development of effective drugs to treat the novel coronavirus infection.

Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne ◽  
Uddhavesh Sonavane ◽  
Asheet Kumar Nath ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Drug Binding ◽  
Ensemble Docking ◽  
Drug Molecules ◽  
Drug Binding Site ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Markov State Modeling ◽  
Viral Polyprotein

<p>The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CL<sup>pro</sup> (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

Comparative docking of SARS-CoV-2 receptors antagonists from repurposing drugs

2020 ◽  
Author(s):  
Micael Davi Lima de Oliveira ◽  
Kelson Mota Teixeira de Oliveira
Keyword(s):  
World Health Organisation ◽  
World Health ◽  
Lung Cells ◽  
The Novel ◽  
High Modulation ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Viral Receptors ◽  
Theoretical Results

According to the World Health Organisation, until 16 June, 2020, the number of confirmed and notified cases of COVID-19 has already exceeded 7.9 million with approximately 434 thousand deaths worldwide. This research aimed to find repurposing antagonists, that may inhibit the activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as partially modulate the ACE2 receptors largely found in lung cells, and reduce viral replication by inhibiting Nsp12 RNA polymerase. Docking molecular simulations were performed among a total of 60 structures, most of all, published in the literature against the novel coronavirus. The theoretical results indicated that, in comparative terms, paritaprevir, ivermectin, ledipasvir, and simeprevir, are among the most theoretical promising drugs in remission of symptoms from the disease. Furthermore, also corroborate indinavir to the high modulation in viral receptors. The second group of promising drugs includes remdesivir and azithromycin. The repurposing drugs HCQ and chloroquine were not effective in comparative terms to other drugs, as monotherapies, against SARS-CoV-2 infection.

scholarly journals The Inhibitory Effects of Plant Derivate Polyphenols on the Main Protease of SARS Coronavirus 2 and Their Structure–Activity Relationship

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1924
Author(s):  
Thi Thanh Hanh Nguyen ◽  
Jong-Hyun Jung ◽  
Min-Kyu Kim ◽  
Sangyong Lim ◽  
Jae-Myoung Choi ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Garlic Extract ◽  
Activity Relationship ◽  
Hydroxyl Group ◽  
Inhibitory Effects ◽  
Structure Activity ◽  
Main Protease ◽  
Ic50 Values ◽  
Km Value ◽  
Novel Coronavirus

The main protease (Mpro) is a major protease having an important role in viral replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that caused the pandemic of 2020. Here, active Mpro was obtained as a 34.5 kDa protein by overexpression in E. coli BL21 (DE3). The optimal pH and temperature of Mpro were 7.5 and 37 °C, respectively. Mpro displayed a Km value of 16 μM with Dabcyl-KTSAVLQ↓SGFRKME-Edans. Black garlic extract and 49 polyphenols were studied for their inhibitory effects on purified Mpro. The IC50 values were 137 μg/mL for black garlic extract and 9–197 μM for 15 polyphenols. The mixtures of tannic acid with puerarin, daidzein, and/or myricetin enhanced the inhibitory effects on Mpro. The structure–activity relationship of these polyphenols revealed that the hydroxyl group in C3′, C4′, C5′ in the B-ring, C3 in the C-ring, C7 in A-ring, the double bond between C2 and C3 in the C-ring, and glycosylation at C8 in the A-ring contributed to inhibitory effects of flavonoids on Mpro.

scholarly journals Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model

2021 ◽  
Vol 22 (13) ◽  
pp. 6910
Author(s):  
Flora Szeri ◽  
Valentina Corradi ◽  
Fatemeh Niaziorimi ◽  
Sylvia Donnelly ◽  
Gwenaëlle Conseil ◽  
...  
Keyword(s):  
Binding Site ◽  
Efflux Pump ◽  
Substrate Binding ◽  
Functional Characterization ◽  
Atp Release ◽  
Homology Model ◽  
Atp Binding ◽  
Atp Binding Site ◽  
Binding Cavity ◽  
Atp Efflux

Inactivating mutations in ABCC6 underlie the rare hereditary mineralization disorder pseudoxanthoma elasticum. ABCC6 is an ATP-binding cassette (ABC) integral membrane protein that mediates the release of ATP from hepatocytes into the bloodstream. The released ATP is extracellularly converted into pyrophosphate, a key mineralization inhibitor. Although ABCC6 is firmly linked to cellular ATP release, the molecular details of ABCC6-mediated ATP release remain elusive. Most of the currently available data support the hypothesis that ABCC6 is an ATP-dependent ATP efflux pump, an un-precedented function for an ABC transporter. This hypothesis implies the presence of an ATP-binding site in the substrate-binding cavity of ABCC6. We performed an extensive mutagenesis study using a new homology model based on recently published structures of its close homolog, bovine Abcc1, to characterize the substrate-binding cavity of ABCC6. Leukotriene C4 (LTC4), is a high-affinity substrate of ABCC1. We mutagenized fourteen amino acid residues in the rat ortholog of ABCC6, rAbcc6, that corresponded to the residues in ABCC1 found in the LTC4 binding cavity. Our functional characterization revealed that most of the amino acids in rAbcc6 corresponding to those found in the LTC4 binding pocket in bovine Abcc1 are not critical for ATP efflux. We conclude that the putative ATP binding site in the substrate-binding cavity of ABCC6/rAbcc6 is distinct from the bovine Abcc1 LTC4-binding site.

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