scholarly journals Identification of SARS-CoV2 Main Protease Coldspots Suitable for Drug Targeting

2020 ◽  
Author(s):  
Navaneethakrishnan Krishnamoorthy ◽  
Khalid Fakhro
Keyword(s):  
Active Site ◽  
Missense Mutations ◽  
The Novel ◽  
X Ray ◽  
X Ray Crystallography ◽  
Main Protease ◽  
New Perspective ◽  
Function Relationship ◽  
Novel Coronavirus ◽  
Relationship Of

Abstract Most attempts to target the novel coronavirus SARS-CoV2 are focusing on the main protease (Mpro) 1,2. We already have access to high resolution 3D-structures of the SARS-CoV2 Mpro, which were developed with inhibitors as co-crystals using X-ray crystallography 3-9. However, >19,000 missense mutations in the Mpro have already been reported 10. The mutations encompassing 282 amino acid positions and these “hotspots” might change the Mpro structure and activity, potentially rendering novel antivirals and vaccines ineffective. Here we identified 24 mutational “coldspots” that have resisted mutation since the virus was first detected. We compared the structure-function relationship of these coldspots with several SARS-CoV2 Mpro X-ray crystal structures. We found that three coldspot residues (Leu141, Phe185 and Gln192) help to form the active site, while six (Gly2, Arg4, Tyr126, Lys137, Leu141 and Leu286) contribute to dimer formation that is required for Mpro activity. Importantly, seven coldpots are conserved among other coronaviruses and available on the surface of the active site and at the dimer interface for targeting. The identification and short list of these coldspots offers a new perspective to target the SARS-CoV2 Mpro while avoiding mutation-based drug resistance.

scholarly journals Identification of Mutation Resistance Coldspots for Targeting the SARS-CoV2 Main Protease

2020 ◽  
Author(s):  
Navaneethakrishnan Krishnamoorthy ◽  
Khalid Fakhro
Keyword(s):  
Active Site ◽  
The Novel ◽  
Dimer Interface ◽  
X Ray ◽  
Main Protease ◽  
New Perspective ◽  
Function Relationship ◽  
Novel Coronavirus ◽  
Relationship Of ◽  
Structure And Activity

Abstract Most attempts to target the novel coronavirus SARS-CoV2 are focusing on the main protease (Mpro) 1-9. However, >19,000 mutations in the Mpro have already been reported 10. The mutations encompassing 282 amino acid positions and these “hotspots” might change the Mpro structure and activity, potentially rendering novel antivirals and vaccines ineffective. Here we identified 24 mutational “coldspots” that have resisted mutation since the virus was first detected. We compared the structure-function relationship of these coldspots with several SARS-CoV2 Mpro X-ray crystal structures. We found that three coldspot residues (Leu141, Phe185 and Gln192) help to form the active site, while six (Gly2, Arg4, Tyr126, Lys137, Leu141 and Leu286) contribute to dimer formation that is required for Mpro activity. The surface of the dimer interface is more resistant to mutations compared to the active site. Interestingly, 16 coldspots are found in conserved patterns when compared with other coronaviruses. Importantly, several conserved coldpots are available on the surface of the active site and at the dimer interface for targeting. The identification and short list of these coldspots offers a new perspective to target the SARS-CoV2 Mpro while avoiding mutation-based drug resistance.

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

2020 ◽  
Author(s):  
Linlin Zhang ◽  
Daizong Lin ◽  
Xinyuanyuan Sun ◽  
Katharina Rox ◽  
Rolf Hilgenfeld
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Atypical Pneumonia ◽  
The Novel ◽  
Replication Complex ◽  
X Ray ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Novel Coronavirus ◽  
Further Development

AbstractA novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also called 3CLpro) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro at 1.75 Å 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-Å 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.

scholarly journals Variable Structural Networks at the Active Site of the SARS-CoV and SARS-CoV2 Main Proteases

2020 ◽  
Author(s):  
Navaneethakrishnan Krishnamoorthy
Keyword(s):  
Active Site ◽  
Molecular Networks ◽  
The Novel ◽  
Active Site Residues ◽  
Molecular Interaction Networks ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Structural Networks ◽  
Key Residues ◽  
Genomic Similarity

The novel coronavirus SARS-CoV2 (CoV2) emerged in December 2019. This virus has 88% genomic similarity with SARS-CoV (CoV), and both viruses largely depend on their main protease (Mpro) to regulate infection. Mpro thus represents an attractive target for anti-SARS drug design. The CoV and CoV2 Mpro are 97% identical at the sequence level, with 12 variable residues, and their X-ray structures appear similar. We thus structurally analysed how these variable residues affect the intra-molecular interactions between key residues in the CoV2 Mpro active-site. Compared to CoV Mpro, the 12 divergent residues in CoV2 Mpro exhibit modified intra-molecular interaction networks that ultimately restructure the molecular micro-environment. These altered networks also indirectly affect the networks of other active-site residues at the entrance (T26, M49 and Q192) and near the catalytic region (F140, H163, H164, M165 and H172) of the Mpro. This suggest CoV2 indirectly (via neighbours) reshape key molecular networks around the Mpro active-site. It seems that the CoV2 Mpro deceives us with its apparent structurally identical to the CoV Mpro while this viral system accumulates mass mutations (12 variable residues) at key positions. Some of these identified CoV2 Mpro networks at the active-site might guide design of efficient CoV2 Mpro inhibitors.

scholarly journals Molecular Docking Unveils Prospective Inhibitors for the SARS-COV-2 Main Protease

2021 ◽  
Vol 50 (5) ◽  
pp. 1473-1483
Author(s):  
Fawad Ahmad ◽  
Saima Ikram ◽  
Jamshaid Ahmad ◽  
Irshad ur Rehman ◽  
Saeed Ullah Khattak ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
3D Structure ◽  
Viral Proteins ◽  
Crystallographic Structure ◽  
X Ray ◽  
Main Protease ◽  
Recent Emergence ◽  
Novel Coronavirus ◽  
3Cl Protease

The recent emergence of a novel coronavirus strain (SARS-CoV-2) has stimulated global efforts to identify potential drugs that target proteins expressed by this novel coronavirus. Among these, the main protease of SARS-CoV-2 (3CL-protease (3CLPro), also known as (MPro) is one of the best choices for the scientists to target. 3CLPro is involved in the processing of polyproteins into mature non-structural viral proteins. An X-ray crystallographic structure (PDB ID 6LU7) of this protein was obtained from the PDB database. ChemDiv libraries of ~80,000 antiviral and ~13,000 coronavirus-targeting molecules were screened against the 3D structure of 3CLPro of SARS-CoV-2. We have identified a panel of molecules that showed an activity and potentially block the active site of the SARS-CoV-2 main protease. These molecules can be investigated further to develop effective virus-inhibiting molecules to treat this highly distressing disease, causing extreme unrest across the globe.

scholarly journals Heavy Atom Detergent/Lipid Combined X-ray Crystallography for Elucidating the Structure-Function Relationships of Membrane Proteins

Membranes ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 823
Author(s):  
Shinya Hanashima ◽  
Takanori Nakane ◽  
Eiichi Mizohata
Keyword(s):  
Membrane Proteins ◽  
Structure Function ◽  
New Technologies ◽  
Heavy Atom ◽  
Protein Structures ◽  
X Ray ◽  
X Ray Crystallography ◽  
Function Relationship ◽  
And Function ◽  
Relationship Of

Membrane proteins reside in the lipid bilayer of biomembranes and the structure and function of these proteins are closely related to their interactions with lipid molecules. Structural analyses of interactions between membrane proteins and lipids or detergents that constitute biological or artificial model membranes are important for understanding the functions and physicochemical properties of membrane proteins and biomembranes. Determination of membrane protein structures is much more difficult when compared with that of soluble proteins, but the development of various new technologies has accelerated the elucidation of the structure-function relationship of membrane proteins. This review summarizes the development of heavy atom derivative detergents and lipids that can be used for structural analysis of membrane proteins and their interactions with detergents/lipids, including their application with X-ray free-electron laser crystallography.

scholarly journals Structural Plasticity of the SARS-CoV-2 3CL Mpro Active Site Cavity Revealed by Room Temperature X-ray Crystallography

2020 ◽  
Author(s):  
Daniel W. Kneller ◽  
Gwyndalyn Phillips ◽  
Hugh M. O'Neill ◽  
Robert Jedrzejczak ◽  
Lucy Stols ◽  
...  
Keyword(s):  
Active Site ◽  
Room Temperature ◽  
Relevant Information ◽  
Docking Studies ◽  
Temperature Structure ◽  
Health Crisis ◽  
X Ray ◽  
X Ray Crystallography ◽  
Main Protease ◽  
Active Site Cavity

Abstract The COVID-19 disease caused by the SARS-CoV-2 Coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL Mpro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL Mpro, revealing the resting structure of the active site and the conformation of the catalytic site cavity. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies.

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.

The role and relationship of mindreading and social attunement in HRI – position statements of interdisciplinary researchers. Workshop HRI'20

2020 ◽  
Author(s):  
Agnieszka Wykowska ◽  
Jairo Pérez-Osorio ◽  
Stefan Kopp
Keyword(s):  
Mental States ◽  
Human Robot Interaction ◽  
Human Interaction ◽  
Artificial Agents ◽  
The Novel ◽  
Robot Interaction ◽  
Novel Coronavirus ◽  
Relationship Of ◽  
The Relationship

This booklet is a collection of the position statements accepted for the HRI’20 conference workshop “Social Cognition for HRI: Exploring the relationship between mindreading and social attunement in human-robot interaction” (Wykowska, Perez-Osorio & Kopp, 2020). Unfortunately, due to the rapid unfolding of the novel coronavirus at the beginning of the present year, the conference and consequently our workshop, were canceled. On the light of these events, we decided to put together the positions statements accepted for the workshop. The contributions collected in these pages highlight the role of attribution of mental states to artificial agents in human-robot interaction, and precisely the quality and presence of social attunement mechanisms that are known to make human interaction smooth, efficient, and robust. These papers also accentuate the importance of the multidisciplinary approach to advance the understanding of the factors and the consequences of social interactions with artificial agents.

scholarly journals Binding of Phosphate and pyrophosphate ions at the active site of human angiogenin as revealed by X-ray crystallography

2001 ◽  
Vol 10 (8) ◽  
pp. 1669-1676 ◽  
Author(s):  
Demetres D. Leonidas ◽  
Gayatri B. Chavali ◽  
Anwar M. Jardine ◽  
Songlin Li ◽  
Robert Shapiro ◽  
...  
Keyword(s):  
Active Site ◽  
X Ray ◽  
X Ray Crystallography

scholarly journals Quinoline and Quinazoline Alkaloids against COVID-19: An In Silico Multitarget Approach

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Esraa M. O. A. Ismail ◽  
Shaza W. Shantier ◽  
Mona S. Mohammed ◽  
Hassan H. Musa ◽  
Wadah Osman ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
The Novel ◽  
Socioeconomic Impacts ◽  
Health Crisis ◽  
Natural Sources ◽  
Angiotensin Converting Enzyme 2 ◽  
Main Protease ◽  
Recent Outbreak ◽  
Novel Coronavirus ◽  
Potential Inhibitors

The recent outbreak of the highly contagious coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 has created a global health crisis with socioeconomic impacts. Although, recently, vaccines have been approved for the prevention of COVID-19, there is still an urgent need for the discovery of more efficacious and safer drugs especially from natural sources. In this study, a number of quinoline and quinazoline alkaloids with antiviral and/or antimalarial activity were virtually screened against three potential targets for the development of drugs against COVID-19. Among seventy-one tested compounds, twenty-three were selected for molecular docking based on their pharmacokinetic and toxicity profiles. The results identified a number of potential inhibitors. Three of them, namely, norquinadoline A, deoxytryptoquivaline, and deoxynortryptoquivaline, showed strong binding to the three targets, SARS-CoV-2 main protease, spike glycoprotein, and human angiotensin-converting enzyme 2. These alkaloids therefore have promise for being further investigated as possible multitarget drugs against COVID-19.

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