An Integrative in Silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

<div><b>Aims</b>: An infectious disease (COVID-19) caused by the coronavirus SARS-CoV-2 emerged in Wuhan, China in December 2019. Currently, SARS-CoV-2 infected more than 9 million people and caused more than 450 000 deaths. Considering the urgent need for novel therapeutics, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we investigated an integrative in silico drug repurposing approach as a valuable tool for rapid selection of potential candidates against SARS-CoV-2 Main Protease (Mpro).</div><div><br></div><div><b>Main methods:</b> To screen FDA-approved drugs, we designed an integrative in silico drug repurposing approach implementing structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data-mining analysis of drug-gene-COVID-19 association.</div><div><br></div><div><b>Key findings:</b> Through the presented approach, 43 candidates with potential inhibitory effect on Mpro were selected and further evaluated according to the predictions of tissue disposition, drug-gene-COVID-19 associations and potential pleiotropic effects. We singled out 9 FDA approved drugs as the most promising for their profiling in COVID-19 drug discovery campaigns. Our results were in agreement with current experimental findings, which validate the applied integrative approach and may support clinical decisions for a novel epidemic wave of COVID-19.</div><div><br></div><div><b>Significance:</b> To the best of our knowledge, this is the first integrative in silico repurposing study for COVID-19 with a clear advantage in linking structure-based molecular modeling of Mpro inhibitors with predictions of tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects of selected candidates.</div>

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In Silico Modeling of FDA-Approved Drugs for Discovery of Therapies Against Neglected Diseases: A Drug Repurposing Approach

In Silico Drug Design ◽

10.1016/b978-0-12-816125-8.00021-3 ◽

2019 ◽

pp. 625-648 ◽

Cited By ~ 2

Author(s):

Carolina L. Belllera ◽

María L. Sbaraglini ◽

Lucas N. Alberca ◽

Juan I. Alice ◽

Alan Talevi

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Neglected Diseases ◽

In Silico Modeling ◽

Approved Drugs ◽

Fda Approved Drugs

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In silico drug repurposing of FDA-approved drugs to predict new inhibitors for drug resistant T315I mutant and wild-type BCR-ABL1: A virtual screening and molecular dynamics study

Journal of Molecular Graphics and Modelling ◽

10.1016/j.jmgm.2017.04.005 ◽

2017 ◽

Vol 74 ◽

pp. 234-240 ◽

Cited By ~ 7

Author(s):

Farzin Sohraby ◽

Milad Bagheri ◽

Masoud Aliyar ◽

Hassan Aryapour

Keyword(s):

Molecular Dynamics ◽

Virtual Screening ◽

In Silico ◽

Drug Repurposing ◽

Drug Resistant ◽

Wild Type ◽

Approved Drugs ◽

Fda Approved Drugs

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In Silico Modeling of FDA-Approved Drugs for Discovery of Anticandida Agents: A Drug-Repurposing Approach

In Silico Drug Design ◽

10.1016/b978-0-12-816125-8.00016-x ◽

2019 ◽

pp. 463-526 ◽

Cited By ~ 1

Author(s):

Sohini Chakraborti ◽

Gayatri Ramakrishnan ◽

Narayanaswamy Srinivasan

Keyword(s):

In Silico ◽

Drug Repurposing ◽

In Silico Modeling ◽

Approved Drugs ◽

Fda Approved Drugs

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Recent Drug-Repurposing-Driven Advances in the Discovery of Novel Antibiotics

Current Medicinal Chemistry ◽

10.2174/0929867325666180706101404 ◽

2019 ◽

Vol 26 (28) ◽

pp. 5363-5388 ◽

Cited By ~ 8

Author(s):

Ananda Kumar Konreddy ◽

Grandhe Usha Rani ◽

Kyeong Lee ◽

Yongseok Choi

Keyword(s):

Drug Discovery ◽

Bacterial Infections ◽

De Novo ◽

Genetic Disorder ◽

Antibacterial Properties ◽

Drug Repurposing ◽

Global Public Health ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Novel Antibiotics

: Drug repurposing is a safe and successful pathway to speed up the novel drug discovery and development processes compared with de novo drug discovery approaches. Drug repurposing uses FDA-approved drugs and drugs that failed in clinical trials, which have detailed information on potential toxicity, formulation, and pharmacology. Technical advancements in the informatics, genomics, and biological sciences account for the major success of drug repurposing in identifying secondary indications of existing drugs. Drug repurposing is playing a vital role in filling the gap in the discovery of potential antibiotics. Bacterial infections emerged as an ever-increasing global public health threat by dint of multidrug resistance to existing drugs. This raises the urgent need of development of new antibiotics that can effectively fight multidrug-resistant bacterial infections (MDRBIs). The present review describes the key role of drug repurposing in the development of antibiotics during 2016–2017 and of the details of recently FDA-approved antibiotics, pipeline antibiotics, and antibacterial properties of various FDA-approved drugs of anti-cancer, anti-fungal, anti-hyperlipidemia, antiinflammatory, anti-malarial, anti-parasitic, anti-viral, genetic disorder, immune modulator, etc. Further, in view of combination therapies with the existing antibiotics, their potential for new implications for MDRBIs is discussed. The current review may provide essential data for the development of quick, safe, effective, and novel antibiotics for current needs and suggest acuity in its effective implications for inhibiting MDRBIs by repurposing existing drugs.

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In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

10.26434/chemrxiv.12598487 ◽

2020 ◽

Author(s):

Tamara Rubilar ◽

Elena Susana Barbieri ◽

Ayelén Gázquez ◽

Marisa Avaro ◽

Mercedes Vera-Piombo ◽

...

Keyword(s):

Sea Urchin ◽

In Silico ◽

De Novo ◽

Drug Repurposing ◽

In Silico Analysis ◽

Promising Alternative ◽

In Silico Docking ◽

Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. <br>

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Drug Repurposing Commonly Against Dengue Virus Capsid and SARS-CoV-2 Nucleocapsid: An in Silico Approach

10.26434/chemrxiv.12611861.v2 ◽

2020 ◽

Author(s):

Debica Mukherjee ◽

Rupesh Roy ◽

UPASANA RAY

Keyword(s):

Dengue Virus ◽

Capsid Protein ◽

In Silico ◽

Rna Binding ◽

Drug Repurposing ◽

Virus Capsid ◽

Approved Drugs ◽

Full Swing ◽

Fda Approved Drugs ◽

Virus Capsid Protein

<p></p><p>In the middle of SARS-CoV-2 pandemic, dengue virus (DENV) is giving a silent warning as the season approaches nearer. There is no specific antiviral against DENV for use in the clinics. Thus, considering these facts we can potentially face both these viruses together increasing the clinical burden. The search for anti-viral drugs against SARS-CoV-2 is in full swing and repurposing of already ‘in-use’ drugs against other diseases or COVID-19 has drawn significant attention. Earlier we had reported few FDA approved anti-viral and anti-microbial drugs that could be tested for binding with SARS-CoV-2 nucleocapsid N terminal domain. We explored the possibility of interactions of the drugs screened for SARS-CoV2 with Dengue virus capsid protein. We report five FDA approved drugs that were seen to be docking onto the SARS-CoV-2 nucleocapsid RNA binding domain, also docking well with DENV capsid protein on the RNA binding site and/or the capsid’s membrane fusion domain. Thus, the present study proposes these five drugs as common antiviral candidates against both SARS-CoV-2 and DENV although the <i>in silico</i> study is subject to further validations.</p><br><p></p>

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In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

10.26434/chemrxiv.12598487.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Tamara Rubilar ◽

Elena Susana Barbieri ◽

Ayelén Gázquez ◽

Marisa Avaro ◽

Mercedes Vera-Piombo ◽

...

Keyword(s):

Sea Urchin ◽

In Silico ◽

De Novo ◽

Drug Repurposing ◽

In Silico Analysis ◽

Promising Alternative ◽

In Silico Docking ◽

Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. <br>

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Repurposing inhibitors for SARS-CoV2 main protease

10.21203/rs.3.rs-41342/v1 ◽

2020 ◽

Author(s):

Kumar Sharp

Keyword(s):

Viral Replication ◽

Active Sites ◽

Drug Repurposing ◽

Chemotherapeutic Drugs ◽

Short Term ◽

Main Protease ◽

Potential Binding ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract SARS-CoV2 main protease is important for viral replication and one of the most potential targets for drug development in this current pandemic. Drug repurposing is a promising field to provide potential short-term acceptable therapy for management of coronavirus till a specific anti-viral for coronavirus is developed. In-silico drug repurposing screening is the current fastest way to repurpose drugs by targeting active sites in fraction of seconds. In this study, SARS-CoV2 main protease is being targeted by 1050 FDA-approved drugs to inhibit its activity thereby interfering with viral replication. Chemotherapeutic drugs and anti-retroviral drugs have shown potential binding as inhibitor. In-vitro and clinical trials required to establish final fact.

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