scholarly journals The SARS-CoV-2 replication-transcription complex is a priority target for broad-spectrum pan-coronavirus drugs

2021 ◽  
Author(s):  
Setayesh Yazdani ◽  
Nicola De Maio ◽  
Yining Ding ◽  
Vijay Shahani ◽  
Nick Goldman ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Disease Burden ◽  
Rna Binding ◽  
Protein Structures ◽  
Drug Binding ◽  
Binding Pockets ◽  
To Come ◽  
Target Binding ◽  
A Site ◽  
Experimental Structure

ABSTRACTIn the absence of effective treatment, COVID-19 is likely to remain a global disease burden. Compounding this threat is the near certainty that novel coronaviruses with pandemic potential will emerge in years to come. Pan-coronavirus drugs – agents active against both SARS-CoV-2 and other coronaviruses – would address both threats. A strategy to develop such broad-spectrum inhibitors is to pharmacologically target binding sites on SARS-CoV-2 proteins that are highly conserved in other known coronaviruses, the assumption being that any selective pressure to keep a site conserved across past viruses will apply to future ones. Here, we systematically mapped druggable binding pockets on the experimental structure of fifteen SARS-CoV-2 proteins and analyzed their variation across twenty-seven α- and β-coronaviruses and across thousands of SARS-CoV-2 samples from COVID-19 patients. We find that the two most conserved druggable sites are a pocket overlapping the RNA binding site of the helicase nsp13, and the catalytic site of the RNA-dependent RNA polymerase nsp12, both components of the viral replication-transcription complex. We present the data on a public web portal (https://www.thesgc.org/SARSCoV2_pocketome/) where users can interactively navigate individual protein structures and view the genetic variability of drug binding pockets in 3D.

scholarly journals Phylogenetic Sequence Variations in Bacterial rRNA Affect Species-Specific Susceptibility to Drugs Targeting Protein Synthesis

2011 ◽  
Vol 55 (9) ◽  
pp. 4096-4102 ◽  
Author(s):  
Subramanian Akshay ◽  
Mihai Bertea ◽  
Sven N. Hobbie ◽  
Björn Oettinghaus ◽  
Dimitri Shcherbakov ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Drug Susceptibility ◽  
Drug Binding ◽  
23S Rrna ◽  
Content Type ◽  
Sequence Variations ◽  
Binding Pockets ◽  
Species Specific ◽  
Peptidyltransferase Center ◽  
A Site

ABSTRACTAntibiotics targeting the bacterial ribosome typically bind to highly conserved rRNA regions with only minor phylogenetic sequence variations. It is unclear whether these sequence variations affect antibiotic susceptibility or resistance development. To address this question, we have investigated the drug binding pockets of aminoglycosides and macrolides/ketolides. The binding site of aminoglycosides is located within helix 44 of the 16S rRNA (A site); macrolides/ketolides bind to domain V of the 23S rRNA (peptidyltransferase center). We have used mutagenesis of rRNA sequences inMycobacterium smegmatisribosomes to reconstruct the different bacterial drug binding sites and to study the effects of rRNA sequence variations on drug activity. Our results provide a rationale for differences in species-specific drug susceptibility patterns and species-specific resistance phenotypes associated with mutational alterations in the drug binding pocket.

scholarly journals Functional characterization of 3D-protein structures informed by human genetic diversity

2017 ◽  
Author(s):  
Michael Hicks ◽  
Istvan Bartha ◽  
Julia di Iulio ◽  
Ruben Abagyan ◽  
J. Craig Venter ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Protein Structures ◽  
3 Dimensional ◽  
Allosteric Sites ◽  
Missense Variation ◽  
Binding Pockets ◽  
Characteristic Features ◽  
Target Binding

Sequence variation data of the human proteome can be used to analyze 3-dimensional (3D) protein structures to derive functional insights. We used genetic variant data from nearly 150,000 individuals to analyze 3D positional conservation in 4,390 protein structures using 481,708 missense and 264,257 synonymous variants. Sixty percent of protein structures harbor at least one intolerant 3D site as defined by significant depletion of observed over expected missense variation. We established an Angstrom-scale distribution of annotated pathogenic missense variants and showed that they accumulate in proximity to the most intolerant 3D sites. Structural intolerance data correlated with experimental functional read-outsin vitro. The 3D structural intolerance analysis revealed characteristic features of ligand binding pockets, orthosteric and allosteric sites. The identification of novel functional 3D sites based on human genetic data helps to validate, rank or predict drug target binding sitesin vivo.

scholarly journals SARS-CoV-2 Pocketome: Severe Acute Respiratory Syndrome Coronavirus 2, Pockets Identification for Antiviral & Antimicrobial Phytomolecules and Drug Repurposing

2020 ◽  
Author(s):  
Akhil Kumar ◽  
Ajit Kumar Shasany
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
De Novo ◽  
Drug Repurposing ◽  
Drug Binding ◽  
Physicochemical Descriptors ◽  
Binding Pockets ◽  
Target Binding ◽  
The Cost ◽  
First Time ◽  
Death Cases

According to WHO, the current Coronavirus disease situation is 8,506,107 confirmed and 455,231 death cases in approx 216 Countries, areas, or territories. For the treatment of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drug repurposing seems to be an effective strategy as it could shorten the time and reduce the cost compared to de novo drug discovery. For that, we need to identify target binding sites. Thus, we have reported for the first time structural druggability assessment for SARS-CoV-2 proteome a pan-druggability prediction based on the open-source pocket detection code fpocket and rank them on the basis of druggability score. We have identified in a total of 433 pockets on the SARS-CoV-2 proteome and characterized by physicochemical descriptors. In which, 47 pockets identified as druggable and 71 as potential drug-binding pockets.

scholarly journals SARS-CoV-2 Pocketome: Severe Acute Respiratory Syndrome Coronavirus 2, Pockets Identification for Antiviral & Antimicrobial Phytomolecules and Drug Repurposing

2020 ◽  
Author(s):  
Akhil Kumar ◽  
Ajit Kumar Shasany
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
De Novo ◽  
Drug Repurposing ◽  
Drug Binding ◽  
Physicochemical Descriptors ◽  
Binding Pockets ◽  
Target Binding ◽  
The Cost ◽  
First Time ◽  
Death Cases

According to WHO, the current Coronavirus disease situation is 8,506,107 confirmed and 455,231 death cases in approx 216 Countries, areas, or territories. For the treatment of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drug repurposing seems to be an effective strategy as it could shorten the time and reduce the cost compared to de novo drug discovery. For that, we need to identify target binding sites. Thus, we have reported for the first time structural druggability assessment for SARS-CoV-2 proteome a pan-druggability prediction based on the open-source pocket detection code fpocket and rank them on the basis of druggability score. We have identified in a total of 433 pockets on the SARS-CoV-2 proteome and characterized by physicochemical descriptors. In which, 47 pockets identified as druggable and 71 as potential drug-binding pockets.

Use of Molecular Dynamics Simulations in Structure-Based Drug Discovery

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Drug Target ◽  
Structural Information ◽  
Drug Binding ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Target Binding ◽  
Dynamics Simulations

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.

RNA secondary structure dependence in METTL3–METTL14 mRNA methylation is modulated by the N-terminal domain of METTL3

2020 ◽  
Vol 402 (1) ◽  
pp. 89-98
Author(s):  
Nathalie Meiser ◽  
Nicole Mench ◽  
Martin Hengesbach
Keyword(s):  
Secondary Structure ◽  
Rna Binding ◽  
Specific Protein ◽  
Structure Dependence ◽  
Terminal Domain ◽  
Methylation Assay ◽  
A Site ◽  
Methylation Activity

AbstractN6-methyladenosine (m6A) is the most abundant modification in mRNA. The core of the human N6-methyltransferase complex (MTC) is formed by a heterodimer consisting of METTL3 and METTL14, which specifically catalyzes m6A formation within an RRACH sequence context. Using recombinant proteins in a site-specific methylation assay that allows determination of quantitative methylation yields, our results show that this complex methylates its target RNAs not only sequence but also secondary structure dependent. Furthermore, we demonstrate the role of specific protein domains on both RNA binding and substrate turnover, focusing on postulated RNA binding elements. Our results show that one zinc finger motif within the complex is sufficient to bind RNA, however, both zinc fingers are required for methylation activity. We show that the N-terminal domain of METTL3 alters the secondary structure dependence of methylation yields. Our results demonstrate that a cooperative effect of all RNA-binding elements in the METTL3–METTL14 complex is required for efficient catalysis, and that binding of further proteins affecting the NTD of METTL3 may regulate substrate specificity.

scholarly journals Structural basis for subtype-specific inhibition of the P2X7 receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Akira Karasawa ◽  
Toshimitsu Kawate
Keyword(s):  
P2x7 Receptor ◽  
Hydrophobic Interactions ◽  
Binding Pocket ◽  
Drug Binding ◽  
Structural Basis ◽  
Atp Binding ◽  
Allosteric Site ◽  
Channel Opening ◽  
A Site ◽  
Novel Drug

The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.

scholarly journals RNA protects a nucleoprotein complex against radiation damage

2016 ◽  
Vol 72 (5) ◽  
pp. 648-657 ◽  
Author(s):  
Charles S. Bury ◽  
John E. McGeehan ◽  
Alfred A. Antson ◽  
Ian Carmichael ◽  
Markus Gerstel ◽  
...  
Keyword(s):  
Radiation Damage ◽  
Rna Binding ◽  
Dose Range ◽  
Protein Molecule ◽  
Highly Sensitive ◽  
Structure Determinations ◽  
Binding Pockets ◽  
Radiation Induced ◽  
Damage Susceptibility ◽  
Dna Complex

Radiation damage during macromolecular X-ray crystallographic data collection is still the main impediment for many macromolecular structure determinations. Even when an eventual model results from the crystallographic pipeline, the manifestations of radiation-induced structural and conformation changes, the so-called specific damage, within crystalline macromolecules can lead to false interpretations of biological mechanisms. Although this has been well characterized within protein crystals, far less is known about specific damage effects within the larger class of nucleoprotein complexes. Here, a methodology has been developed whereby per-atom density changes could be quantified with increasing dose over a wide (1.3–25.0 MGy) range and at higher resolution (1.98 Å) than the previous systematic specific damage study on a protein–DNA complex. Specific damage manifestations were determined within the largetrpRNA-binding attenuation protein (TRAP) bound to a single-stranded RNA that forms a belt around the protein. Over a large dose range, the RNA was found to be far less susceptible to radiation-induced chemical changes than the protein. The availability of two TRAP molecules in the asymmetric unit, of which only one contained bound RNA, allowed a controlled investigation into the exact role of RNA binding in protein specific damage susceptibility. The 11-fold symmetry within each TRAP ring permitted statistically significant analysis of the Glu and Asp damage patterns, with RNA binding unexpectedly being observed to protect these otherwise highly sensitive residues within the 11 RNA-binding pockets distributed around the outside of the protein molecule. Additionally, the method enabled a quantification of the reduction in radiation-induced Lys and Phe disordering upon RNA binding directly from the electron density.

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