scholarly journals Drug Repurposing Approach Targeted Against Main Protease of SARS-CoV-2 Exploiting ‘Neighbourhood Behaviour’ in 3D Protein Structural Space and 2D Chemical Space of Small Molecules

2020 ◽  
Author(s):  
Sohini Chakraborti ◽  
Narayanaswamy Srinivasan
Keyword(s):  
Small Molecules ◽  
Chemical Space ◽  
Three Dimensional ◽  
International Health ◽  
Drug Repurposing ◽  
Self Medication ◽  
Drug Candidates ◽  
Main Protease ◽  
Structural Space ◽  
Prior Approval

<p>The current global crisis due to COVID-19 has almost brought normal life to standstill in most parts of the world. With our research interest on repurposing known drugs/drug candidates targeting various diseases, we decided to analyse the available data on the deadly pathogen that has already taken thousands of lives since its outbreak in China in December 2019. Our host institute is now shutdown and we are confining ourselves to our homes with limited access to computational resources. Using a simple <i>in silico</i> approach based on the principle of ‘neighbourhood behaviour’ in three-dimensional (3D) space and two-dimensional (2D) space of protein and small molecules respectively, we have identified potential drugs/drug candidates which can be repurposed against protein targets encoded by the SARS-CoV-2 genome. Based on our preliminary analysis, we have so far prioritized more than 20 known drugs/drug candidates which might elucidate anti-coronavirus properties by binding to main protease of the pathogen. These drugs belong to diverse therapeutic areas such as antiviral, anticancer, antibacterial agents etc. Notably, apart from many synthetic molecules, our analysis also hints that phytochemicals obtained from vinca plant (vinca alkaloids) and camptotheca tree (camptothecin and its derivatives) have the potential to bind to main protease of SARS-CoV-2. In-depth investigation on our findings are currently on-going. Here we are presenting the results we obtained so far. The sole purpose of making these preliminary findings openly available to the community is for the experimental biologists and biomedical researchers to investigate our predictions in experimental set ups and for the clinicians to evaluate the potential of these findings for anti-COVID-19 treatment. <b>Our findings should only be used for research purposes and we strongly urge that no individual should interpret these findings for any self-diagnosis or self-medication without the prior approval from competent international health/medical regulatory agencies.</b></p>

scholarly journals Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

2020 ◽  
Author(s):  
Mahmudul Hasan ◽  
Md Sorwer Alam Parvez ◽  
Kazi Faizul Azim ◽  
Abdus Shukur Imran ◽  
Topu Raihan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Repurposing ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Drug Candidates ◽  
Target Drug ◽  
Global Pandemic ◽  
Main Protease ◽  
Docking Approach ◽  
Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

scholarly journals Consensus Virtual Screening of Dark Chemical Matter and Food Chemicals Uncover Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Marisa G. Santibáñez-Morán ◽  
Edgar López-López ◽  
Fernando D. Prieto-Martínez ◽  
Norberto Sánchez-Cruz ◽  
Jose L. Medina-Franco
Keyword(s):  
Virtual Screening ◽  
Chemical Space ◽  
Experimental Testing ◽  
Consensus Approach ◽  
Computational Tools ◽  
Drug Candidates ◽  
Main Protease ◽  
Selection For ◽  
Potential Inhibitors ◽  
Chemical Matter

The COVID-19 pandemic caused by SARS-CoV-2 has claimed more than 380,000 lives Worldwide and more than 6.5 million people are infected. Unfortunately, there is no drug or vaccine for the treatment of COVID-19. The increasing information available of key molecular targets of SARS-CoV-2 and active compounds against related coronavirus facilitates computational tools to rapidly suggest drug candidates for the treatment of COVID-19. As part of a global effort to fight the COVID-19 pandemic, herein we report a consensus virtual screening of large collections of food chemicals and compounds classified as Dark Chemical Matter. The rationale is to complement global efforts and explore regions of the chemical space currently underexplored. The consensus approach included combining similarity searching with various queries and fingerprints, molecular docking with two docking programs, and ADMETox profiling. We propose three compounds commercially available that were sent to experimental testing. We disclose the full list of virtual screening hits that can be subject to additional selection for acquisition or synthesis and experimental testing. This manuscript will be updated when the experimental testing of the selected compounds becomes available.

scholarly journals Repurposing drugs against main protease of SARS-CoV-2: mechanism based insights supported by available laboratory and clinical data

2020 ◽  
Author(s):  
Sohini Chakraborti ◽  
Sneha Bheemireddy ◽  
Narayanaswamy Srinivasan
Keyword(s):  
Clinical Data ◽  
International Health ◽  
Therapeutic Interventions ◽  
Integrative Approach ◽  
Self Medication ◽  
Docking Simulations ◽  
Global Pandemic ◽  
Viral Proteases ◽  
Main Protease ◽  
Approved Drugs

<p></p><p>The ongoing global pandemic of COVID-19 has brought life to almost stand still with implementations of lockdown and social distancing as some of the preventive measures in the absence of any approved specific therapeutic interventions. To combat this crisis, research community world-wide are falling back on the existing repertoire of approved/investigational drugs to probe into their anti-coronavirus properties. In this report, we have described our unique efforts in identifying potential drugs that could be repurposed against main protease of SARS-CoV-2 (SARS-CoV-2 M<sup>pro</sup>). To achieve this goal, we have primarily exploited the principles of ‘neighbourhood behaviour’ in protein 3-D (workflow-I) and chemical 2-D structural space (workflow-II) coupled with docking simulations and insights into the possible mode of actions of the selected candidates from available literature. Such an integrative approach culminated in prioritizing 29 potential repurpose-able agents (20 approved drugs and 9 investigational molecules) against SARS-CoV-2 M<sup>pro</sup>. Apart from the approved/investigational anti-viral drugs, other notable hits include anti-bacterial, anti-inflammatory, anti-cancer and anti-coagulant drugs. Our analysis suggests that some of these drugs have the potential to simultaneously modulate the functions of viral proteins and host response system. Interestingly, many of these identified candidates (12 molecules from workflow-I and several molecules belonging to the chemical classes of alkaloids, tetracyclines, peptidomimetics from workflow-II) are suggested to possess anti-viral properties which are supported by laboratory and clinical data. Further, this work opens a new avenue of research to probe into the molecular mechanism of action of many drugs which are known to demonstrate anti-viral activity but are so far not known to target viral proteases. <b>Our findings should only be used for research purposes and we strongly urge that no individual should interpret these findings for any self-diagnosis or self-medication without the prior approval from competent international health/medical regulatory agencies.</b></p><p></p>

scholarly journals Prioritization of Potential Drugs Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Yanjin Li ◽  
Yu Zhang ◽  
Yikai Han ◽  
Tengfei Zhang ◽  
Ranran Du
Keyword(s):  
Large Scale ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Neural Activities ◽  
Main Protease ◽  
Global Threat ◽  
Potential Inhibitors ◽  
Molecular Patterns ◽  
Effective Drugs ◽  
Large Scale Screening

<p> Since its outbreak in 2019, the acute respiratory syndrome caused by SARS-Cov-2 has become a severe global threat to human. The lack of effective drugs strongly limits the therapeutic treatment against this pandemic disease. Here we employed a computational approach to prioritize potential inhibitors that directly target the core enzyme of SARS-Cov-2, the main protease, which is responsible for processing the viral RNA-translated polyprotein into functional proteins for viral replication. Based on a large-scale screening of over 13, 000 drug-like molecules, we have identified the most potential drugs that may suffice drug repurposing for SARS-Cov-2. Importantly, the second top hit is Beclabuvir, a known replication inhibitor of hepatitis C virus (HCV), which is recently reported to inhibit SARS-Cov-2 as well. We also noted several neurotransmitter-related ligands among the top candidates, suggesting a novel molecular similarity between this respiratory syndrome and neural activities. Our approach not only provides a comprehensive list of prioritized drug candidates for SARS-Cov-2, but also reveals intriguing molecular patterns that are worth future explorations.</p>

scholarly journals Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

2020 ◽  
Author(s):  
Mahmudul Hasan ◽  
Md Sorwer Alam Parvez ◽  
Kazi Faizul Azim ◽  
Abdus Shukur Imran ◽  
Topu Raihan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Repurposing ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Drug Candidates ◽  
Target Drug ◽  
Global Pandemic ◽  
Main Protease ◽  
Docking Approach ◽  
Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

scholarly journals Virtual High Throughput Screening Based Prediction of Potential Drugs for COVID-19

2020 ◽  
Author(s):  
Sekhar Talluri
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Viral Infections ◽  
Genomic Sequence ◽  
Reproduction Number ◽  
Three Dimensional ◽  
Drug Repurposing ◽  
Dimensional Structure ◽  
Main Protease ◽  
Approved Drugs

SARS-CoV-2 is a betacoronavirus that was first identified during the Wuhan COVID-19 epidemic in 2019. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease (Mpro) are available. The reported structure of the target Mpro was utilized in this study to identify potential drugs for COVID-19 using virtual high throughput screening. The results of this study confirm earlier preliminary reports based on studies of homologs that some of the drugs approved for treatment of other viral infections also have the potential for treatment of COVID-19. Approved anti-viral drugs that target proteases were ranked for potential effectiveness against COVID-19 and novel candidates for drug repurposing were identified.

Prioritization of Potential Drugs Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Yanjin Li ◽  
Yu Zhang ◽  
Yikai Han ◽  
Tengfei Zhang ◽  
Ranran Du
Keyword(s):  
Large Scale ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Neural Activities ◽  
Main Protease ◽  
Global Threat ◽  
Potential Inhibitors ◽  
Molecular Patterns ◽  
Effective Drugs ◽  
Large Scale Screening

<p> Since its outbreak in 2019, the acute respiratory syndrome caused by SARS-Cov-2 has become a severe global threat to human. The lack of effective drugs strongly limits the therapeutic treatment against this pandemic disease. Here we employed a computational approach to prioritize potential inhibitors that directly target the core enzyme of SARS-Cov-2, the main protease, which is responsible for processing the viral RNA-translated polyprotein into functional proteins for viral replication. Based on a large-scale screening of over 13, 000 drug-like molecules, we have identified the most potential drugs that may suffice drug repurposing for SARS-Cov-2. Importantly, the second top hit is Beclabuvir, a known replication inhibitor of hepatitis C virus (HCV), which is recently reported to inhibit SARS-Cov-2 as well. We also noted several neurotransmitter-related ligands among the top candidates, suggesting a novel molecular similarity between this respiratory syndrome and neural activities. Our approach not only provides a comprehensive list of prioritized drug candidates for SARS-Cov-2, but also reveals intriguing molecular patterns that are worth future explorations.</p>

Recent Advances in the Synthetic Chemistry of Bicyclo[1.1.1]pentane

Synlett ◽  
2018 ◽  
Vol 30 (01) ◽  
pp. 1-11 ◽  
Author(s):  
Junichiro Kanazawa ◽  
Masanobu Uchiyama
Keyword(s):  
Water Solubility ◽  
Chemical Space ◽  
Direct Synthesis ◽  
Three Dimensional ◽  
High Water ◽  
Synthetic Chemistry ◽  
Drug Candidates ◽  
Recent Advances ◽  
Wide Range ◽  
Phenyl Rings

Utilization of three-dimensional cyclic scaffolds is important in modern drug discovery, both to provide greater opportunities for optimizing drug candidates and to expand the available chemical space of drugs. Among these scaffolds, bicyclo[1.1.1]pentane (BCP) is a high-value bioisostere for 1,4-disubstituted phenyl rings, internal alkynes, and the tert-butyl group, generally offering high passive permeability, high water solubility, and improved metabolic stability. However, the lack of methods for functionalizing BCP remains a significant challenge, and in particular, a versatile strategy for synthesizing a wide range of unsymmetrically 1,3-difunctionalized BCP derivatives has been lacking. In this account, we review recent advances in the synthetic chemistry of BCP, focusing especially on our recently developed radical multicomponent carboamination of [1.1.1]propellane.1 Introduction2 Overview of the Synthetic Chemistry of [1.1.1]Propellane, the Most Promising Precursor of Bicyclo[1.1.1]pentane3 Recent Advances in the Synthetic Chemistry of Unsymmetrically 1,3-Disubstituted Bicyclo[1.1.1]pentane Derivatives4 Radical Multicomponent Carboamination of [1.1.1]Propellane Permits Direct Synthesis of 3-Substituted Bicyclo[1.1.1]pent-1-ylamine Derivatives5 Conclusion

scholarly journals Repurposing drugs against main protease of SARS-CoV-2: mechanism based insights supported by available laboratory and clinical data

2020 ◽  
Author(s):  
Sohini Chakraborti ◽  
Sneha Bheemireddy ◽  
Narayanaswamy Srinivasan
Keyword(s):  
Clinical Data ◽  
International Health ◽  
Therapeutic Interventions ◽  
Integrative Approach ◽  
Self Medication ◽  
Docking Simulations ◽  
Global Pandemic ◽  
Viral Proteases ◽  
Main Protease ◽  
Approved Drugs

<p></p><p>The ongoing global pandemic of COVID-19 has brought life to almost stand still with implementations of lockdown and social distancing as some of the preventive measures in the absence of any approved specific therapeutic interventions. To combat this crisis, research community world-wide are falling back on the existing repertoire of approved/investigational drugs to probe into their anti-coronavirus properties. In this report, we have described our unique efforts in identifying potential drugs that could be repurposed against main protease of SARS-CoV-2 (SARS-CoV-2 M<sup>pro</sup>). To achieve this goal, we have primarily exploited the principles of ‘neighbourhood behaviour’ in protein 3-D (workflow-I) and chemical 2-D structural space (workflow-II) coupled with docking simulations and insights into the possible mode of actions of the selected candidates from available literature. Such an integrative approach culminated in prioritizing 29 potential repurpose-able agents (20 approved drugs and 9 investigational molecules) against SARS-CoV-2 M<sup>pro</sup>. Apart from the approved/investigational anti-viral drugs, other notable hits include anti-bacterial, anti-inflammatory, anti-cancer and anti-coagulant drugs. Our analysis suggests that some of these drugs have the potential to simultaneously modulate the functions of viral proteins and host response system. Interestingly, many of these identified candidates (12 molecules from workflow-I and several molecules belonging to the chemical classes of alkaloids, tetracyclines, peptidomimetics from workflow-II) are suggested to possess anti-viral properties which are supported by laboratory and clinical data. Further, this work opens a new avenue of research to probe into the molecular mechanism of action of many drugs which are known to demonstrate anti-viral activity but are so far not known to target viral proteases. <b>Our findings should only be used for research purposes and we strongly urge that no individual should interpret these findings for any self-diagnosis or self-medication without the prior approval from competent international health/medical regulatory agencies.</b></p><p></p>

scholarly journals Drug Repurposing to Identify Therapeutics Against COVID 19 with SARS-Cov-2 Spike Glycoprotein and Main Protease as Targets: An in Silico Study

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Sadasivan C
Keyword(s):  
In Silico ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Drug Candidates ◽  
Protein Receptor ◽  
Main Protease ◽  
In Silico Study ◽  
Molecular Modeling And Docking ◽  
Different Parts

<p>The total cases of novel corona virus (SARS-CoV-2) infections is more than one million and total deaths recorded is more than fifty thousand. The research for developing vaccines and drugs against SARS-CoV-2 is going on in different parts of the world. Aim of the present study was to identify potential drug candidates against SARS-CoV-2 from existing drugs using <i>in silico</i> molecular modeling and docking. The targets for the present study was the spike protein and the main protease of SARS-CoV-2. The study was able to identify some drugs that can either bind to the spike protein receptor binding domain or the main protease of SARS-CoV-2. These include some of the antiviral drugs. These drugs might have the potential to inhibit the infection and viral replication.</p>

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