scholarly journals Repurposing of Drugs for SARS-CoV-2 Using Inverse Docking Fingerprints

2021 ◽  
Vol 9 ◽  
Author(s):  
Marko Jukič ◽  
Katarina Kores ◽  
Dušanka Janežič ◽  
Urban Bren
Keyword(s):  
Middle East ◽  
Drug Repurposing ◽  
Biological Evaluation ◽  
Middle East Respiratory Syndrome ◽  
Protein Database ◽  
Pathogenic Potential ◽  
Direct Acting Antiviral ◽  
Main Protease ◽  
Repurposed Drugs ◽  
Direct Acting

Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 is a virus that belongs to the Coronaviridae family. This group of viruses commonly causes colds but possesses a tremendous pathogenic potential. In humans, an outbreak of SARS caused by the SARS-CoV virus was first reported in 2003, followed by 2012 when the Middle East respiratory syndrome coronavirus (MERS-CoV) led to an outbreak of Middle East respiratory syndrome (MERS). Moreover, COVID-19 represents a serious socioeconomic and global health problem that has already claimed more than four million lives. To date, there are only a handful of therapeutic options to combat this disease, and only a single direct-acting antiviral, the conditionally approved remdesivir. Since there is an urgent need for active drugs against SARS-CoV-2, the strategy of drug repurposing represents one of the fastest ways to achieve this goal. An in silico drug repurposing study using two methods was conducted. A structure-based virtual screening of the FDA-approved drug database on SARS-CoV-2 main protease was performed, and the 11 highest-scoring compounds with known 3CLpro activity were identified while the methodology was used to report further 11 potential and completely novel 3CLpro inhibitors. Then, inverse molecular docking was performed on the entire viral protein database as well as on the Coronaviridae family protein subset to examine the hit compounds in detail. Instead of target fishing, inverse docking fingerprints were generated for each hit compound as well as for the five most frequently reported and direct-acting repurposed drugs that served as controls. In this way, the target-hitting space was examined and compared and we can support the further biological evaluation of all 11 newly reported hits on SARS-CoV-2 3CLpro as well as recommend further in-depth studies on antihelminthic class member compounds. The authors acknowledge the general usefulness of this approach for a full-fledged inverse docking fingerprint screening in the future.

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 Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

2020 ◽  
Author(s):  
Ancy Iruthayaraj ◽  
Sivanandam Magudeeswaran ◽  
Kumaradhas Poomani
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Free Energy ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Binding Mechanism ◽  
Main Protease ◽  
Repurposed Drugs ◽  
Hiv 1

<p>Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (M<sup>pro</sup>). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 M<sup>pro</sup>. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of M<sup>pro</sup> enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of M<sup>pro</sup> and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This <i>in silico</i> study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 M<sup>pro</sup> enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.</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 COVID-19: The Immune Responses and Clinical Therapy Candidates

2020 ◽  
Vol 21 (15) ◽  
pp. 5559 ◽  
Author(s):  
Sareh Zhand ◽  
Marie Saghaeian Jazi ◽  
Saeed Mohammadi ◽  
Roozbeh Tarighati Rasekhi ◽  
Ghassem Rostamian ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Middle East ◽  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
Drug Administration ◽  
Food And Drug Administration ◽  
Middle East Respiratory Syndrome ◽  
Adults And Children ◽  
Repurposed Drugs ◽  
Present Understanding

The pandemic of coronavirus disease 2019 (COVID-19), with rising numbers of patients worldwide, presents an urgent need for effective treatments. To date, there are no therapies or vaccines that are proven to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several potential candidates or repurposed drugs are under investigation, including drugs that inhibit SARS-CoV-2 replication and block infection. The most promising therapy to date is remdesivir, which is US Food and Drug Administration (FDA) approved for emergency use in adults and children hospitalized with severe suspected or laboratory-confirmed COVID-19. Herein we summarize the general features of SARS-CoV-2’s molecular and immune pathogenesis and discuss available pharmacological strategies, based on our present understanding of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infections. Finally, we outline clinical trials currently in progress to investigate the efficacy of potential therapies for COVID-19.

scholarly journals Hepatitis C Virus Infection in Persons Who Inject Drugs in the Middle East and North Africa: Intervention Strategies

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1363
Author(s):  
Jag H. Khalsa ◽  
Poonam Mathur
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Middle East ◽  
North Africa ◽  
Intervention Strategies ◽  
Addiction Medicine ◽  
Mena Region ◽  
Persons Who Inject Drugs ◽  
Direct Acting Antiviral ◽  
Direct Acting

There is a high incidence and prevalence of hepatitis C viral infection in persons with or without substance use disorders (SUDs) in the Middle East and North Africa (MENA) region, but only a small number receive comprehensive care. Highly effective direct-acting antiviral (DAA) medications are available at substantially lower costs; however, complete elimination of the hepatitis C virus (HCV) can only be achieved if integrated care strategies target those at highest risk for HCV infection and transmission and improve access to care. Due to the high prevalence of SUD in the MENA region, strategies to eliminate HCV must focus on integrated healthcare across multiple subspecialties, including addiction medicine, psychiatry, infectious diseases, hepatology, and social work. In this invited manuscript, we review the epidemiology of HCV in the MENA region and highlight intervention strategies to attain the WHO’s goal of HCV eradication by 2030.

scholarly journals Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

2020 ◽  
Author(s):  
Ancy Iruthayaraj ◽  
Sivanandam Magudeeswaran ◽  
Kumaradhas Poomani
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Free Energy ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Binding Mechanism ◽  
Main Protease ◽  
Repurposed Drugs ◽  
Hiv 1

<p>Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (M<sup>pro</sup>). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 M<sup>pro</sup>. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of M<sup>pro</sup> enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of M<sup>pro</sup> and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This <i>in silico</i> study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 M<sup>pro</sup> enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.</p>

scholarly journals Drug repurposing against MERS CoV and SARS-COV-2 PLpro in silico

2020 ◽  
Author(s):  
Abdo Elfiky ◽  
Noha Ibrahim ◽  
Wael Elshemey
Keyword(s):  
Molecular Docking ◽  
Middle East ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Cysteine Protease ◽  
In Silico ◽  
Drug Repurposing ◽  
Middle East Respiratory Syndrome ◽  
Interaction Pattern ◽  
Structural Protein

Abstract Aim: The Middle East Respiratory Syndrome coronavirus (MERS-CoV) and COVID-19 cause severe acute, deadly, pneumonia. Papain-like protease (PLpro), is HCoV cysteine protease encoded within the Non-Structural protein 3. Materials and Methods: Molecular docking is performed to test the binding performance of six protease inhibitors against MERS CoV and SARS-CoV-2 PLpro. Results: The compound, GRL-0667, shows the highest binding affinity to MERS CoV PLpro, while Grazoprevir shows the highest binding affinity against HCV NS3. Moreover, the interaction pattern in the case of HCV NS3 is the same as in the case of coronaviruses. Conclusion: The present study shows the ability of some anti-SARS CoV and anti-HCV NS3 drugs to inhibit MERS CoV PLpro, interestingly, including the newly emerged SARS-COV-2 PLpro.

scholarly journals Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay

2021 ◽  
Vol 118 (30) ◽  
pp. e2024302118
Author(s):  
Woo Dae Jang ◽  
Sangeun Jeon ◽  
Seungtaek Kim ◽  
Sang Yup Lee
Keyword(s):  
Virtual Screening ◽  
Synergistic Effects ◽  
Drug Repurposing ◽  
Vero Cells ◽  
False Positives ◽  
Human Lung Cells ◽  
Main Protease ◽  
General Drug ◽  
Repurposed Drugs ◽  
Approved Drugs

The COVID-19 pandemic caused by SARS-CoV-2 is an unprecedentedly significant health threat, prompting the need for rapidly developing antiviral drugs for the treatment. Drug repurposing is currently one of the most tangible options for rapidly developing drugs for emerging and reemerging viruses. In general, drug repurposing starts with virtual screening of approved drugs employing various computational methods. However, the actual hit rate of virtual screening is very low, and most of the predicted compounds are false positives. Here, we developed a strategy for virtual screening with much reduced false positives through incorporating predocking filtering based on shape similarity and postdocking filtering based on interaction similarity. We applied this advanced virtual screening approach to repurpose 6,218 approved and clinical trial drugs for COVID-19. All 6,218 compounds were screened against main protease and RNA-dependent RNA polymerase of SARS-CoV-2, resulting in 15 and 23 potential repurposed drugs, respectively. Among them, seven compounds can inhibit SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, show anti-SARS-CoV-2 activities in human lung cells, Calu-3. Notably, the activity of omipalisib is 200-fold higher than that of remdesivir in Calu-3. Furthermore, three drug combinations, omipalisib/remdesivir, tipifarnib/omipalisib, and tipifarnib/remdesivir, show strong synergistic effects in inhibiting SARS-CoV-2. Such drug combination therapy improves antiviral efficacy in SARS-CoV-2 infection and reduces the risk of each drug’s toxicity. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating COVID-19 and other viruses.

Massive Infektion und alveolare Schädigung der humanen Lunge durch das Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Pneumologie ◽  
2015 ◽  
Vol 69 (04) ◽  
Author(s):  
A Becher ◽  
J von Recum ◽  
K Schierhorn ◽  
T Wolff ◽  
M Tönnies ◽  
...  
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome

Aerogen übertragene Infektionskrankheiten bei Kindern auf Reisen

2018 ◽  
Vol 18 (06) ◽  
pp. 422-426
Author(s):  
C. Rau ◽  
J. Lindert ◽  
S. Kotsias-Konopelska ◽  
R. Kobbe
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome ◽  
Bakterielle Infektionen ◽  
Saisonale Influenza

ZusammenfassungErkrankungen der Atemwege gehören zu den häufigsten Gesundheitsproblemen von Kindern und treten regelhaft auch während und nach Reisen auf. Virale Atemwegsinfektionen können die Reisefähigkeit von Kindern – und damit auch ihren Angehörigen – ungünstig beeinflussen, beispielsweise durch Fieber, bronchiale Obstruktion und Schwierigkeiten beim Druckausgleich während des Fliegens durch Schwellungen und Sekretionen der Schleimhäute und der eustachi‘schen Röhre. Zu den reisemedizinisch relevanten aerogen übertragenen Krankheiten zählen neben banalen, viralen Erkältungen auch potenziell schwer verlaufende Viruserkrankungen, allen voran die saisonale Influenza und die Masern, sowie bakterielle Infektionen durch Meningokokken und die Tuberkulose. Gegen einige dieser Erkrankungen stehen effektive Impfstoffe zur Verfügung. Auch seltene, schwer verlaufende Atemwegsinfektionen, die unter bestimmten epidemiologischen Umständen außerhalb Europas erworben werden können, sollen im Folgenden exemplarisch an den Erkrankungen Middle East respiratory syndrome (MERS) und der Histoplasmose dargestellt werden.

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