scholarly journals A Comprehensive SARS-CoV-2 Genomic Analysis Identifies Potential Targets for Drug Repurposing

2020 ◽  
Author(s):  
Nithishwer Mouroug Anand ◽  
Devang Haresh Liya ◽  
Arpit Kumar Pradhan ◽  
Nitish Tayal ◽  
Abhinav Bansal ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Clinical Trials ◽  
Viral Genome ◽  
Drug Targets ◽  
Population Level ◽  
Haplotype Network ◽  
Small Time ◽  
Ligand Complex ◽  
Global Spread ◽  
Conserved Genes

<p><b>Background: </b>The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) initially reported in December 2019 in Wuhan City, China causing pneumonia-like symptoms and other respiratory tract illness. It’s higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. With 6,529,240 cases and about 385,264 deaths, this pandemic has become a global concern with certain drugs and vaccines failing at later clinical trials.</p> <p> </p> <p><b>Materials and Methods: </b>Phylogenetic Analysis, Haplotype Network, Analysis of conserved genes and population-level variants, Using conserved genes as targets for drug designing, Docking studies and Molecular Dynamics (MD) simulations to predict the stability of Drug-Ligand Complex.</p> <p> </p> <p><b>Results: </b>We identified the most common haplotypes from the haplotype network and at least seven different clusters were found signifying seven different viral lineages across the globe. We studied the mutation frequency across the SARS-CoV-2 viral genome. The conserved genes and population level variants were analyzed and NSP10, Nucleoprotein, Plpro and 3CLpro which were conserved at the highest threshold were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs which are suggested for further pre-clinical and clinical trials.</p> <p> </p> <p><b>Significance: </b>This particular study provides a comprehensive targeting of the conserved genes as a novel approach for drug targeting. The conserved gene approach could also be of a big use while designing vaccines and cure. Mutations in the viral genome make the designing of the drugs a challenging task which has a higher risk of failure at later clinical trials. This approach of targeting the stable genes for drug discovery would provide a better therapeutic approach and confidence in the successive clinical trials. We also identified the global level spread of SARS-CoV-2 and mutation frequencies across the viral genome. Our study gives insights of the origin and global spread of the SARS-CoV-2. The data provided in this study can further be used by other groups to understand and combat Covid 19.</p>

scholarly journals A Comprehensive SARS-CoV-2 Genomic Analysis Identifies Potential Targets for Drug Repurposing

2020 ◽  
Author(s):  
Nithishwer Mouroug Anand ◽  
Devang Haresh Liya ◽  
Arpit Kumar Pradhan ◽  
Nitish Tayal ◽  
Abhinav Bansal ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Clinical Trials ◽  
Viral Genome ◽  
Drug Targets ◽  
Population Level ◽  
Haplotype Network ◽  
Small Time ◽  
Ligand Complex ◽  
Global Spread ◽  
Conserved Genes

<p><b>Background: </b>The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) initially reported in December 2019 in Wuhan City, China causing pneumonia-like symptoms and other respiratory tract illness. It’s higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. With 6,529,240 cases and about 385,264 deaths, this pandemic has become a global concern with certain drugs and vaccines failing at later clinical trials.</p> <p> </p> <p><b>Materials and Methods: </b>Phylogenetic Analysis, Haplotype Network, Analysis of conserved genes and population-level variants, Using conserved genes as targets for drug designing, Docking studies and Molecular Dynamics (MD) simulations to predict the stability of Drug-Ligand Complex.</p> <p> </p> <p><b>Results: </b>We identified the most common haplotypes from the haplotype network and at least seven different clusters were found signifying seven different viral lineages across the globe. We studied the mutation frequency across the SARS-CoV-2 viral genome. The conserved genes and population level variants were analyzed and NSP10, Nucleoprotein, Plpro and 3CLpro which were conserved at the highest threshold were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs which are suggested for further pre-clinical and clinical trials.</p> <p> </p> <p><b>Significance: </b>This particular study provides a comprehensive targeting of the conserved genes as a novel approach for drug targeting. The conserved gene approach could also be of a big use while designing vaccines and cure. Mutations in the viral genome make the designing of the drugs a challenging task which has a higher risk of failure at later clinical trials. This approach of targeting the stable genes for drug discovery would provide a better therapeutic approach and confidence in the successive clinical trials. We also identified the global level spread of SARS-CoV-2 and mutation frequencies across the viral genome. Our study gives insights of the origin and global spread of the SARS-CoV-2. The data provided in this study can further be used by other groups to understand and combat Covid 19.</p>

scholarly journals A comprehensive SARS-CoV-2 genomic analysis identifies potential targets for drug repurposing

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248553
Author(s):  
Nithishwer Mouroug Anand ◽  
Devang Haresh Liya ◽  
Arpit Kumar Pradhan ◽  
Nitish Tayal ◽  
Abhinav Bansal ◽  
...  
Keyword(s):  
Drug Targets ◽  
Acute Infection ◽  
Genomic Analysis ◽  
Drug Repurposing ◽  
Population Level ◽  
Haplotype Network ◽  
Small Time ◽  
Structural Protein ◽  
Genome Variability ◽  
Conserved Genes

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) was initially reported in December 2019 in Wuhan City, China. This acute infection caused pneumonia-like symptoms and other respiratory tract illness. Its higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. One of the major concerns involving the SARS-COV-2 is the mutation rate, which enhances the virus evolution and genome variability, thereby making the design of therapeutics difficult. In this study, we identified the most common haplotypes from the haplotype network. The conserved genes and population level variants were analysed. Non-Structural Protein 10 (NSP10), Nucleoprotein, Papain-like protease (Plpro or NSP3) and 3-Chymotrypsin like protease (3CLpro or NSP5), which were conserved at the highest threshold, were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs, which are suggested for further pre-clinical and clinical trials. This particular study provides a comprehensive targeting of the conserved genes. We also identified the mutation frequencies across the viral genome.

scholarly journals 520. Longitudinal Analysis of SARS-CoV-2 Viruses in Hospitalized Adults

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S325-S326
Author(s):  
Lacy Simons ◽  
Ramon Lorenzo-Redondo ◽  
Hannah Nam ◽  
Scott C Roberts ◽  
Michael G Ison ◽  
...  
Keyword(s):  
Viral Load ◽  
Genome Sequencing ◽  
Viral Genome ◽  
Temporal Dynamics ◽  
Population Level ◽  
Hospital Staff ◽  
Therapeutic Interventions ◽  
Viral Loads ◽  
Qrt Pcr ◽  
Over Time

Abstract Background The rapid spread of SARS-CoV-2, the causative agent of Coronavirus disease 2019 (COVID-19), has been accompanied by the emergence of viral mutations, some of which may have distinct virological and clinical consequences. While whole genome sequencing efforts have worked to map this viral diversity at the population level, little is known about how SARS-CoV-2 may diversify within a host over time. This is particularly important for understanding the emergence of viral resistance to therapeutic interventions and immune pressure. The goal of this study was to assess the change in viral load and viral genome sequence within patients over time and determine if these changes correlate with clinical and/or demographic parameters. Methods Hospitalized patients admitted to Northwestern Memorial Hospital with a positive SARS-CoV-2 test were enrolled in a longitudinal study for the serial collection of nasopharyngeal specimens. Swabs were administered to patients by hospital staff every 4 ± 1 days for up to 32 days or until the patients were discharged. RNA was extracted from each specimen and viral loads were calculated by quantitative reverse transcriptase PCR (qRT-PCR). Specimens with qRT-PCR cycle threshold values less than or equal to 30 were subject to whole viral genome sequencing by reverse transcription, multiplex PCR, and deep sequencing. Variant populations sizes were estimated and subject to phylogenetic analysis relative to publicly available SARS-CoV-2 sequences. Sequence and viral load data were subsequently correlated to available demographic and clinical data. Results 60 patients were enrolled from March 26th to June 20th, 2020. We observed an overall decrease in nasopharyngeal viral load over time across all patients. However, the temporal dynamics of viral load differed on a patient-by-patient basis. Several mutations were also observed to have emerged within patients over time. Distribution of SARS-CoV-2 viral loads in serially collected nasopharyngeal swabs in hospitalized adults as determined by qRT-PCR. Samples were collected every 4 ± 1 days (T#1–8) and viral load is displayed by log(copy number). Conclusion These data indicate that SARS-CoV-2 viral loads in the nasopharynx decrease over time and that the virus can accumulate mutations during replication within individual patients. Future studies will examine if some of these mutations may provide fitness advantages in the presence of therapeutic and/or immune selective pressures. Disclosures Michael G. Ison, MD MS, AlloVir (Consultant)

scholarly journals Analysis of Clinical Trials on Therapies for Prostate Cancer in Mainland China and Globally from 2010 to 2020

2021 ◽  
Vol 11 ◽  
Author(s):  
Kun Chen ◽  
Kehua Jiang ◽  
Lannan Tang ◽  
Xiaolong Chen ◽  
Jianxin Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Drug Targets ◽  
Checkpoint Inhibitors ◽  
Mainland China ◽  
World Population ◽  
Large Patient ◽  
Future Direction ◽  
Long Acting ◽  
Targeted Chemotherapeutics

The overall aging of the world population has contributed to the continuous upward trend in the incidence of prostate cancer (PC). Trials on PC therapy have been extensively performed, but no study has analyzed the overall trends and characteristics of these trials, especially for those carried out in China. This study aimed to provide insights on the future direction of drug development in PC, thus supplying essential supportive data for stakeholders, including researchers, patients, investors, clinicians, and pharmaceutical industry. The details of the clinical trials of drug therapies for PC during January 1, 2010, to January 1, 2020, were collected from Pharmaprojects. A total of 463 clinical trials on different therapies with 132 different drugs were completed. The long-acting endocrine therapy with few side effects, radiotherapy combined with immune checkpoint inhibitors, gene-targeted chemotherapeutics, and novel immunotherapeutic products changed the concept of PC treatment. In mainland China, 31 trials with 19 drugs have been completed in the 10 assessment years. China has initiated a few trials investigating a limited number of drug targets, centered in a markedly uneven geographical distribution of leading clinical trial units; hence, the development of PC drugs has a long way to go. Given the large patient pool, China deserves widespread attention for PC drug research and development. These findings might have a significant impact on scientific research and industrial investment.

scholarly journals Reliability of Wastewater Analysis for Monitoring COVID-19 Incidence Revealed by a Long-Term Follow-Up Study

2021 ◽  
Vol 1 ◽  
Author(s):  
Rafael Sanjuán ◽  
Pilar Domingo-Calap
Keyword(s):  
Viral Genome ◽  
Population Level ◽  
Wastewater Analysis ◽  
Disease Notification ◽  
Follow Up Study ◽  
Long Term Follow Up ◽  
Low Incidence ◽  
Rna Concentration

Wastewater-based epidemiology has been used for monitoring human activities and waterborne pathogens. Although wastewaters can also be used for tracking SARS-CoV-2 at the population level, the reliability of this approach remains to be established, especially for early warning of outbreaks. We collected 377 samples from different treatment plants processing wastewaters of &gt;1 million inhabitants in Valencia, Spain, between April 2020 and March 2021. Samples were cleaned, concentrated, and subjected to RT-qPCR to determine SARS-CoV-2 concentrations. These data were compared with cumulative disease notification rates over 7 and 14 day periods. We amplified SARS-CoV-2 RNA in 75% of the RT-qPCRs, with an estimated detection limit of 100 viral genome copies per liter (gc/L). SARS-CoV-2 RNA concentration correlated strongly with disease notification rates over 14-day periods (Pearson r = 0.962, P &lt; 0.001). A concentration &gt;1000 gc/L showed &gt;95% sensitivity and specificity as an indicator of more than 25 new cases per 100,000 inhabitants. Albeit with slightly higher uncertainty, these figures were reproduced using a 7-day period. Time series were similar for wastewaters data and declared cases, but wastewater RNA concentrations exhibited transient peaks that were not observed in declared cases and preceded major outbreaks by several weeks. In conclusion, wastewater analysis provides a reliable tool for monitoring COVID-19, particularly at low incidence values, and is not biased by asymptomatic cases. Moreover, this approach might reveal previously unrecognized features of COVID-19 transmission.

scholarly journals Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome

2016 ◽  
Author(s):  
Zheng Zhao ◽  
Lei Xie ◽  
Philip E. Bourne
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Protein Kinases ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Allosteric Inhibitors ◽  
Type Iii ◽  
Human Kinome

AbstractProtein kinases are critical drug targets for treating a large variety of human diseases. Type-I and type-II kinase inhibitors frequently exhibit off-target toxicity or lead to mutation acquired resistance. Two highly specific allosteric type-III MEK-targeted drugs, Trametinib and Cobimetinib, offer a new approach. Thus, understanding the binding mechanism of existing type-III kinase inhibitors will provide insights for designing new type-III kinase inhibitors. In this work we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors. We propose that the helix-folding activation loop is a hallmark allosteric binding site for type-III inhibitors. Subsequently we screened and predicted allosteric binding sites across the human kinome, suggesting other kinases as potential targets suitable for type-III inhibitors. Our findings will provide new insights into the design of potent and selective kinases inhibitors.Author SummaryHuman protein kinases represent a large protein family relevant to many diseases, especially cancers, and have become important drug targets. However, developing the desired selective kinase-targeted inhibitors remain challenging. Kinase allosteric inhibitors provide that opportunity, but, to date, few have been designed other than MEK inhibitors. To more efficiently develop kinase allosteric inhibitors, we systematically studied the binding mode of the MEK type-III allosteric kinase inhibitors using structural system pharmacology and molecular dynamics approaches. New insights into the binding mode and mechanism of type-III inhibitors were revealed that may facilitate the design of new prospective type-III kinase inhibitors.

How to Assign AMBER Parameters to Desmond-generated System with viparr4 v1

2021 ◽  
Author(s):  
Thilo Mast ◽  
Dmitry Lupyan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Force Fields ◽  
Third Party ◽  
Ligand Complex ◽  
Software Suite ◽  
Dynamics Simulations

This tutorial partially copies steps from How to Assign CHARMM Parameters to Desmond-generated System with viparr4 but differs in the parametrization steps. You can use the Schrödinger software suite to prepare systems for molecular dynamics simulations, however, only the OPLS _2005 and OPLS4 force fields can be automatically assigned. This tutorial will show you how to use Desmond with third-party force fields like AMBER, using the Viparr utility from D.E. Shaw Research. You will prepare a protein-ligand complex, generate custom AMBER parameters for the ligand, and use the Viparr utility to convert the generated AMBER parameters into a viparr-formatted template, that can be used for simulations. You can find the input files for this tutorial here:

Using molecular docking and molecular dynamics to investigate protein-ligand interactions

2021 ◽  
Vol 35 (08) ◽  
pp. 2130002
Author(s):  
Connor J. Morris ◽  
Dennis Della Corte
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Drug Discovery ◽  
State Of The Art ◽  
Ligand Complex ◽  
Protein Ligand Interactions ◽  
Art Methods ◽  
Ligand Interactions ◽  
Docking Calculations ◽  
Ligand Bond

Molecular docking and molecular dynamics (MD) are powerful tools used to investigate protein-ligand interactions. Molecular docking programs predict the binding pose and affinity of a protein-ligand complex, while MD can be used to incorporate flexibility into docking calculations and gain further information on the kinetics and stability of the protein-ligand bond. This review covers state-of-the-art methods of using molecular docking and MD to explore protein-ligand interactions, with emphasis on application to drug discovery. We also call for further research on combining common molecular docking and MD methods.

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