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

<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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Identification of new inhibitors of the toxoplasma gondii by using in-silico drug repurposing

10.1101/560284 ◽

2019 ◽

Author(s):

Mosleh Kadkhodamohammadi ◽

Milad Jaberi ◽

Reza Babaei akerdi ◽

Masoud Aliyar

Keyword(s):

Protein Kinase ◽

Toxoplasma Gondii ◽

In Silico ◽

Drug Repurposing ◽

Dependent Protein Kinase ◽

Calcium Dependent ◽

Dependent Protein ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Calcium Dependent Protein Kinase

AbstractIntroductionThe common treatment for toxoplasmosis was pyrimethamine. In recent years, it has been found that this parasite is getting resistant to this treatment, therefore urgent alternative treatments are needed.Material and MethodsIn this study, by using drug repurposing and in silico methods we tried to make a selective treatment by inhibiting the Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii which doesn’t exist in mammalians. We screened the FDA approved drugs by molecular docking and after ranking them by their binding energies and inspecting the top scored ones, we chose Cefpiramide, Ceftriaxone and Cefotiam as the hit compounds. After that, we used molecular dynamics simulations to test the hit compounds in a much more realistic environment.ResultsBy analyzing the results, we found that all of the hit compounds and good and can bind strongly to the active site of the protein. Therefore, they can be potential candidates for inhibiting Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii.ConclusionMoreover, because the predicted compounds are FDA approved drugs, their toxicity profiles are well known and their newly predicted use can be tested in clinical trials.

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

10.26434/chemrxiv.12611861 ◽

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 FDA-Approved Drug Repurposing to Find the Possible Treatment of Coronavirus Disease-19 (COVID-19)

10.26434/chemrxiv.12340718 ◽

2020 ◽

Cited By ~ 2

Author(s):

Kumar Sharp ◽

Dr. Shubhangi Dange

Keyword(s):

In Silico ◽

Drug Target ◽

Drug Repurposing ◽

Target Interaction ◽

Compound Libraries ◽

Anti Cancer ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Large Compound ◽

Better Than

Identification of potential drug-target interaction for approved drugs serves as the basis of repurposing drugs. Studies have shown polypharmacology as common phenomenon. In-silico approaches help in screening large compound libraries at once which could take years in a laboratory. We screened a library of 1050 FDA-approved drugs against spike glycoprotein of SARS-CoV2 in-silico. Anti-cancer drugs have shown good binding affinity which is much better than hydroxychloroquine and arbidol. We have also introduced a hypothesis named “Bump” hypothesis which and be developed further in field of computational biology.

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In-Silico FDA-Approved Drug Repurposing to Find the Possible Treatment of Coronavirus Disease-19 (COVID-19)

10.26434/chemrxiv.12340718.v1 ◽

2020 ◽

Author(s):

Kumar Sharp ◽

Dr. Shubhangi Dange

Keyword(s):

In Silico ◽

Drug Target ◽

Drug Repurposing ◽

Target Interaction ◽

Compound Libraries ◽

Anti Cancer ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Large Compound ◽

Better Than

Identification of potential drug-target interaction for approved drugs serves as the basis of repurposing drugs. Studies have shown polypharmacology as common phenomenon. In-silico approaches help in screening large compound libraries at once which could take years in a laboratory. We screened a library of 1050 FDA-approved drugs against spike glycoprotein of SARS-CoV2 in-silico. Anti-cancer drugs have shown good binding affinity which is much better than hydroxychloroquine and arbidol. We have also introduced a hypothesis named “Bump” hypothesis which and be developed further in field of computational biology.

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

10.26434/chemrxiv.12578672 ◽

2020 ◽

Author(s):

Nemanja Djokovic ◽

Dusan Ruzic ◽

Teodora Djikic ◽

Sandra Cvijic ◽

Jelisaveta Ignjatovic ◽

...

Keyword(s):

In Silico ◽

De Novo ◽

Drug Repurposing ◽

Pleiotropic Effects ◽

Integrative Approach ◽

Pbpk Modelling ◽

Main Protease ◽

Tissue Disposition ◽

Approved Drugs ◽

Fda Approved Drugs

<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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