Approach Towards Drugs Repurposing: Docking Studies with Multiple Target Proteins Associated with SARS-CoV-2

Viral Proteases ◽

Docking Tool ◽

Free Energy Of Binding ◽

<p>The current pandemic outbreak of COVID-19 due to viral infections by SARS-CoV-2 is now become associated with severe commotion on global healthcare and economy. In this extreme situation when vaccine or drugs against COVID-19 are not available, the only quick and feasible therapeutic alternative would be the drug repurposing approach. In the present work, <i>in silico</i> screening of some antiviral and antiprotozoal drugs using Autodock docking tool was performed. Two known antiviral drugs sorivudine and noricumazole B are predicted to bind to the active site of the viral proteases namely cysteine like protease or 3CL protease (3CLpro) and papain like protease (PLpro) respectively with a highly favorable free energy of binding. Further, the promising molecules were subjected for checking their activity on other molecular targets like spike protein S1, RNA dependent RNA polymerase (RdRp) and angiotensin converting enzyme 2 (ACE2) receptor. But the compounds were found not effective on rest other molecular targets. </p>

Approach Towards Drugs Repurposing: Docking Studies with Multiple Target Proteins Associated with SARS-CoV-2

10.26434/chemrxiv.12469172.v1 ◽

2020 ◽

Author(s):

Shiwani Rana ◽

Meghali Panwar ◽

Kalyan Sundar Ghosh

Keyword(s):

Viral Infections ◽

Molecular Targets ◽

Drug Repurposing ◽

Docking Studies ◽

Extreme Situation ◽

Viral Proteases ◽

Docking Tool ◽

Free Energy Of Binding ◽

<p>The current pandemic outbreak of COVID-19 due to viral infections by SARS-CoV-2 is now become associated with severe commotion on global healthcare and economy. In this extreme situation when vaccine or drugs against COVID-19 are not available, the only quick and feasible therapeutic alternative would be the drug repurposing approach. In the present work, <i>in silico</i> screening of some antiviral and antiprotozoal drugs using Autodock docking tool was performed. Two known antiviral drugs sorivudine and noricumazole B are predicted to bind to the active site of the viral proteases namely cysteine like protease or 3CL protease (3CLpro) and papain like protease (PLpro) respectively with a highly favorable free energy of binding. Further, the promising molecules were subjected for checking their activity on other molecular targets like spike protein S1, RNA dependent RNA polymerase (RdRp) and angiotensin converting enzyme 2 (ACE2) receptor. But the compounds were found not effective on rest other molecular targets. </p>

Docking studies with multiple molecular targets associated with SARSCoV-2 for drug repurposing

Coronaviruses ◽

10.2174/2666796701999201216111613 ◽

2020 ◽

Vol 01 ◽

Author(s):

Shiwani Rana ◽

Meghali Panwar ◽

Kalyan Sundar Ghosh

Keyword(s):

Viral Infections ◽

Molecular Targets ◽

Drug Repurposing ◽

Docking Studies ◽

New Drugs ◽

In Silico Screening ◽

Viral Proteases ◽

Free Energy Of Binding ◽

Background: The current pandemic outbreak of COVID-19 due to viral infections by SARS-CoV-2 is now become associated with severe commotion on global healthcare and economy. Objective: In this extreme situation when vaccine or effective new drugs against COVID-19 are not available, the only quick and feasible therapeutic alternative would be the drug repurposing approach. Method: In the present work, in silico screening of some antiviral and antiprotozoal drugs was performed based on docking using Autodock. Results: Two known antiviral drugs sorivudine and noricumazole B are predicted to bind to the active site of the viral proteases namely cysteine like protease or 3CL protease (3CLpro) and papain like protease (PLpro) respectively with a highly favorable free energy of binding. Further, the promising molecules were subjected for checking their activity on other molecular targets in SARS-CoV-2 like spike protein S1, RNA dependent RNA polymerase (RdRp) and angiotensin converting enzyme 2 (ACE2) receptor. But the compounds were found non-effective on rest other molecular targets. Conclusion: Sorivudine alone or a combination of sorivudine and noricumazole B may be administered to impede viral replication though the predicted drug likeliness of noricumazole B is not very much satisfactory. These observations are solely based on the results from blind docking with protein molecules and that need to be further corroborated with experimental results.

Virtual Screening of Naturally Occurring Antiviral Molecules for SARS-CoV-2 Mitigation Using Docking Tool on Multiple Molecular Targets

10.26434/chemrxiv.12403940.v1 ◽

2020 ◽

Author(s):

Shiwani Rana ◽

Sanjay Sharma ◽

Kalyan Sundar Ghosh

Keyword(s):

Molecular Targets ◽

World Health ◽

Huge Number ◽

Infected People ◽

Naturally Occurring ◽

The World ◽

Docking Tool ◽

Health Organization ◽

<p>The coronavirus catastrophe (COVID-19) caused by a novel strain of coronavirus (SARS-CoV-2) has turned the world upside down at an unprecedented level and has been declared as a pandemic by World Health Organization (WHO). It has resulted huge number of fatalities and infections due to the severe lower respiratory tract sickness in the infected people. Research across the world is in progress to identify inhibitors against various molecular targets associated with this viral infection. Among these targets, a very important one is a cysteine like protease or 3CL protease (3CLpro) and that is required for the replication of the virus. In the present study, initially we have investigated the potential of twenty naturally occurring antiviral molecules to function as inhibitors against the activity of main viral protease (3CLpro) so as to put a halt on viral replication. The investigation has been carried out through docking of the molecules with 3CLpro. Based on the results, three most potential molecules (bilobetin, ginkgetin and sciadopitysin) have been screened. Further these molecules were subjected for checking their activity on other molecular targets like a papain like protease (PLpro), spike protein S1, RNA dependent RNA polymerase (RdRp), angiotensin converting enzyme 2 (ACE2) receptor. In addition to 3CLpro inhibition, ginkgetin was predicted as an inhibitor of PLpro also. But none of these three compounds was found effective on rest other molecular targets. </p>

Virtual Screening of Naturally Occurring Antiviral Molecules for SARS-CoV-2 Mitigation Using Docking Tool on Multiple Molecular Targets

10.26434/chemrxiv.12403940 ◽

2020 ◽

Author(s):

Shiwani Rana ◽

Sanjay Sharma ◽

Kalyan Sundar Ghosh

Keyword(s):

Molecular Targets ◽

World Health ◽

Huge Number ◽

Infected People ◽

Naturally Occurring ◽

The World ◽

Docking Tool ◽

Health Organization ◽

<p>The coronavirus catastrophe (COVID-19) caused by a novel strain of coronavirus (SARS-CoV-2) has turned the world upside down at an unprecedented level and has been declared as a pandemic by World Health Organization (WHO). It has resulted huge number of fatalities and infections due to the severe lower respiratory tract sickness in the infected people. Research across the world is in progress to identify inhibitors against various molecular targets associated with this viral infection. Among these targets, a very important one is a cysteine like protease or 3CL protease (3CLpro) and that is required for the replication of the virus. In the present study, initially we have investigated the potential of twenty naturally occurring antiviral molecules to function as inhibitors against the activity of main viral protease (3CLpro) so as to put a halt on viral replication. The investigation has been carried out through docking of the molecules with 3CLpro. Based on the results, three most potential molecules (bilobetin, ginkgetin and sciadopitysin) have been screened. Further these molecules were subjected for checking their activity on other molecular targets like a papain like protease (PLpro), spike protein S1, RNA dependent RNA polymerase (RdRp), angiotensin converting enzyme 2 (ACE2) receptor. In addition to 3CLpro inhibition, ginkgetin was predicted as an inhibitor of PLpro also. But none of these three compounds was found effective on rest other molecular targets. </p>

In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

10.26434/chemrxiv.12049590.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Yogesh Kumar ◽

Harvijay Singh

Keyword(s):

Virtual Screening ◽

Active Site ◽

Viral Infections ◽

Drug Repurposing ◽

Docking Study ◽

Docking Studies ◽

Main Protease ◽

Novel Coronavirus ◽

Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

10.26434/chemrxiv.12049590 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yogesh Kumar ◽

Harvijay Singh

Keyword(s):

Virtual Screening ◽

Active Site ◽

Viral Infections ◽

Drug Repurposing ◽

Docking Study ◽

Docking Studies ◽

Main Protease ◽

Novel Coronavirus ◽

Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

Understanding Severe Acute Respiratory Syndrome Coronavirus 2 Replication to Design Efficient Drug Combination Therapies

Intervirology ◽

10.1159/000512141 ◽

2020 ◽

Vol 63 (1-6) ◽

pp. 2-9

Author(s):

Joseph T. Ortega ◽

Jose L. Zambrano ◽

Beata Jastrzebska ◽

Ferdinando Liprandi ◽

Hector R. Rangel ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Viral Infections ◽

Therapeutic Targets ◽

Drug Repurposing ◽

Antiviral Effect ◽

Cell Interaction ◽

Combination Therapies ◽

Early Stages ◽

Antiviral Compounds ◽

Viral Proteases

<b><i>Background:</i></b> The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease COVID-19 has strongly encouraged the search for antiviral compounds. Most of the evaluated drugs against SARS-CoV-2 derive from drug repurposing of Food and Drug Administration-approved molecules. These drugs have as target three major processes: (1) early stages of virus-cell interaction, (2) viral proteases, and (3) the viral RNA-dependent RNA polymerase. <b><i>Summary:</i></b> This review focused on the basic principles of virology and pharmacology to understand the importance of early stages of virus-cell interaction as therapeutic targets and other main processes vital for SARS-CoV-2 replication. Furthermore, we focused on describing the main targets associated with SARS-CoV-2 antiviral therapy and the rationale of drug combinations for efficiently suppressing viral replication. <b><i>Key Messages:</i></b> We hypothesized that blocking of both entry mechanisms could allow a more effective antiviral effect compared to the partial results obtained with chloroquine or its derivatives alone. This approach, already used to achieve an antiviral effect higher than that offered by every single drug administered separately, has been successfully applied in several viral infections such as HIV and HCV. This review will contribute to expanding the perception of the possible therapeutic targets in SARS-CoV-2 infection and highlight the benefits of using combination therapies.

Drug repurposing using similarity-based target prediction, docking studies and scaffold hopping of lefamulin

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201201113712 ◽

2020 ◽

Vol 17 ◽

Author(s):

Shikha Sharma ◽

Shweta Sharma ◽

Vaishali Pathak ◽

Parwinder Kaur ◽

Rajesh Kumar Singh

Keyword(s):

In Silico ◽

Target Prediction ◽

Drug Repurposing ◽

Docking Studies ◽

Target Protein ◽

Future Perspective ◽

Antibacterial Drug ◽

Scaffold Hopping ◽

Target Proteins ◽

Renin Inhibitors

Aim: To investigate and validate the potential target proteins for drug repurposing of newly FDA approved antibacterial drug. Background: Drug repurposing is the process of assigning indications for drugs other than the one(s) that they were initially developed for. Discovery of entirely new indications from already approved drugs is highly lucrative as it minimizes the pipeline of the drug development process by reducing time and cost. In silico driven technologies made it possible to analyze molecules for different target proteins which are not yet explored. Objective: To analyze possible targets proteins for drug repurposing of lefamulin and their validation. Also, in silico prediction of novel scaffolds from lefamulin has been performed for assisting medicinal chemists in future drug design. Methods: A similarity-based prediction tool was employed for predicting target protein and further investigated using docking studies on PDB ID: 2V16. Besides, various in silico tools were employed for prediction of novel scaffolds from lefamulin using scaffold hopping technique followed by evaluation with various in silico parameters viz., ADME, synthetic accessibility and PAINS. Results: Based on the similarity and target prediction studies, renin is found as the most probable target protein for lefamulin. Further, validation studies using docking of lefamulin revealed the significant interactions of lefamulin with the binding pocket of the target protein. Also, three novel scaffolds were predicted using scaffold hopping technique and found to be in the limit to reduce the chances of drug failure in the physiological system during the last stage approval process. Conclusion: To encapsulate the future perspective, lefamulin may assist in the development of the renin inhibitors and, also three possible novel scaffolds with good pharmacokinetic profile can be developed into both as renin inhibitors and for bacterial infections.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524920666201021164805 ◽

2020 ◽

Vol 20 ◽

Author(s):

Tanay Dalvi ◽

Bhaskar Dewangan ◽

Rudradip Das ◽

Jyoti Rani ◽

Suchita Dattatray Shinde ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Development ◽

Molecular Targets ◽

Drug Repurposing ◽

Phase Iii ◽

Complex Nature ◽

New Drug ◽

Development Pipeline ◽

Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.