Evidence for Substrate Binding-Induced Zwitterion Formation in the Catalytic Cys-His Dyad of the SARS-CoV Main Protease

Biochemistry ◽  
2014 ◽  
Vol 53 (37) ◽  
pp. 5930-5946 ◽  
Author(s):  
Alexander Paasche ◽  
Andreas Zipper ◽  
Simon Schäfer ◽  
John Ziebuhr ◽  
Tanja Schirmeister ◽  
...  
Keyword(s):  
Substrate Binding ◽  
Main Protease ◽  
Zwitterion Formation

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.

Influence of charge configuration on substrate binding to SARS-CoV-2 main protease

2021 ◽  
Author(s):  
Natalia Díaz ◽  
Dimas Suárez
Keyword(s):  
Computer Simulations ◽  
Active Site ◽  
Substrate Binding ◽  
Binding Ability ◽  
Main Protease ◽  
Charge Configuration

Computer simulations describe the substrate binding ability of two alternative protonation states for the 3CLpro active site.

scholarly journals Computational estimation of potential inhibitors from known drugs against the main protease of SARS-CoV-2

RSC Advances ◽  
2021 ◽  
Vol 11 (28) ◽  
pp. 17478-17486
Author(s):  
Nguyen Minh Tam ◽  
Minh Quan Pham ◽  
Nguyen Xuan Ha ◽  
Pham Cam Nam ◽  
Huong Thi Thu Phung
Keyword(s):  
Binding Site ◽  
Substrate Binding ◽  
Substrate Binding Site ◽  
Computational Estimation ◽  
Main Protease ◽  
Critical Residues ◽  
Approved Drugs ◽  
Potential Inhibitors

Approved drugs predicted to interact with critical residues in the substrate-binding site of SARS-CoV-2 Mpro can be promising inhibitors.

scholarly journals Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Anas Shamsi ◽  
Taj Mohammad ◽  
Saleha Anwar ◽  
Mohamed F. AlAjmi ◽  
Afzal Hussain ◽  
...  
Keyword(s):  
Substrate Binding ◽  
Clinical Manifestations ◽  
Binding Pocket ◽  
Good Choice ◽  
Sufficient Evidence ◽  
Substrate Binding Pocket ◽  
Structure Based Drug Design ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.

Screening for Potential Traditional Herbal Inhibitors Against 3-Chymotrypsin-Like Main Protease (3CLpro) from Four Different Coronaviruses-: An in-silico Approach

Coronaviruses ◽  
2021 ◽  
Vol 02 ◽  
Author(s):  
Prachi Singh ◽  
Ardra P ◽  
Hariprasad V.R. ◽  
Babu U.V. ◽  
Mohamed Rafiq ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Broad Spectrum ◽  
Active Site ◽  
Dissociation Constants ◽  
Substrate Binding ◽  
Binding Pocket ◽  
Health Concern ◽  
Ocimum Sanctum ◽  
Prunella Vulgaris ◽  
Main Protease

Background: The recent outbreak of the COVID-19 pandemic has raised a global health concern due to the unavailability of any vaccines or drugs. The repurposing of traditional herbs with broad-spectrum anti-viral activity can be explored to control or prevent a pandemic. Objective: The 3-chymotrypsin-like main protease (3CLpro), also referred to as the “Achilles’ heel” of the coronaviruses (CoVs), is highly conserved among CoVs and is a potential drug target. 3CLpro is essential for the virus’s life cycle. The objective of the study was to screen and identify broad-spectrum natural phytoconstituents against the conserved active site and substrate-binding site of 3CLpro of HCoVs. Methods: Herein, we applied the computational strategy based on molecular docking to identify potential phytoconstituents for the non-covalent inhibition of the main protease 3CLpro from four different CoVs, namely, SARS-CoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Results: Our study shows that natural phytoconstituents in Triphala (a blend of Emblica Officinalis fruit, Terminalia bellerica fruit, and Terminalia chebula fruit), namely chebulagic acid, chebulinic acid, and elagic acid, exhibited the highest binding affinity and lowest dissociation constants (Ki), against the conserved 3CLpro main protease of SARSCoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Besides, phytoconstituents of other herbs like Withania somnifera, Glycyrrhiza glabra, Hyssopus officinalis, Camellia sinensis, Prunella vulgaris, and Ocimum sanctum also showed good binding affinity and lower Ki against the active site of 3CLpro. The top-ranking phytoconstituents’ binding interactions clearly showed a strong and stable interactions with amino acid residues in the catalytic dyad (CYS-HIS) and substrate-binding pocket of the 3CLpro main proteases. Conclusion: This study provides a valuable scaffold for repurposing traditional herbs with anti-CoV activity to combat SARS-CoV-2 and other HCoVs until the discovery of new therapies.

Fibronexus-Like Adhesion Sites are Present at the Invasive Zones of Human Epidermoid Carcinomas

1982 ◽  
Vol 40 ◽  
pp. 106-109
Author(s):  
Irwin I. Singer
Keyword(s):  
Cell Cycle ◽  
Serum Concentration ◽  
Substrate Binding ◽  
High Serum ◽  
Adhesion Sites ◽  
Substrate Adhesion ◽  
Focal Contacts ◽  
Adhesion Complex ◽  
Low Serum

Our previous results indicate that two types of fibronectin-cytoskeletal associations may be formed at the fibroblast surface: dorsal matrixbinding fibronexuses generated in high serum (5% FBS) cultures, and ventral substrate-adhering units formed in low serum (0.3% FBS) cultures. The substrate-adhering fibronexus consists of at least vinculin (VN) and actin in its cytoplasmic leg, and fibronectin (FN) as one of its major extracellular components. This substrate-adhesion complex is localized in focal contacts, the sites of closest substratum approach visualized with interference reflection microscopy, which appear to be the major points of cell-tosubstrate adhesion. In fibroblasts, the latter substrate-binding complex is characteristic of cultures that are arrested at the G1 phase of the cell cycle due to the low serum concentration in their medium. These arrested fibroblasts are very well spread, flattened, and immobile.

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.

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