scholarly journals An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Docking Simulations ◽  
Approved Drugs

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Nilotinib and Imatinib bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.

scholarly journals An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

2020 ◽  
Author(s):  
Alfonso Trezza ◽  
Daniele Iovinelli ◽  
Filippo Prischi ◽  
Annalisa Santucci ◽  
Ottavia Spiga
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Spike Protein ◽  
Effective Vaccine ◽  
Docking Simulations ◽  
Approved Drugs

Abstract The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.Authors Alfonso Trezza and Daniele Iovinelli contributed equally to this work.

scholarly journals Data-Driven Drug Repurposing for COVID-19

2020 ◽  
Author(s):  
Raghvendra Mall ◽  
Abdurrahman Elbasir ◽  
Hossam Al Meer ◽  
Sanjay Chawla ◽  
Ehsan Ullah
Keyword(s):  
Clinical Trials ◽  
De Novo ◽  
Drug Repurposing ◽  
Binding Energies ◽  
Protein Activity ◽  
De Novo Drug Design ◽  
Docking Simulations ◽  
Antibiotic Drugs ◽  
Approved Drugs ◽  
Ranked List

<div>Motivation: A global effort is underway to identify drugs for the treatment of COVID-19. Since de novo drug design is an extremely long, time-consuming, and expensive process, efforts are underway to discover existing drugs that can be</div><div>repurposed for COVID-19.</div><div><br></div><div>Model: We propose a machine learning representation framework that uses deep learning induced vector embeddings of drugs and viral proteins as features to predict drug-viral protein activity. The prediction model in-turn is used to build an ensemble framework to rank approved drugs based on their ability to inhibit the three main proteases (enzymes) of the SARS-COV-2 virus.</div><div><br></div><div>Results: We identify a ranked list of 19 drugs as potential targets including 7 antivirals, 6 anticancer, 3 antibiotics, 2 antimalarial, and 1 antifungal. Several drugs, such as Remdesivir, Lopinavir, Ritonavir, and Hydroxychloroquine, in our ranked list, are currently in clinical trials. Moreover, through molecular docking simulations, we demonstrate that majority of the anticancer and antibiotic drugs in our ranked list have low binding energies and thus high binding affinity with the 3CL-pro protease of SARS-COV-2 virus.</div><div><br></div><div>Disclaimer: Our models are computational and the drugs suggested should not be taken for treating COVID-19 without a doctor's advice, as further wet-lab research and clinical trials are essential to elucidate their efficacy for this purpose.</div>

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

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>

scholarly journals Data-Driven Drug Repurposing for COVID-19

2020 ◽  
Author(s):  
Raghvendra Mall ◽  
Abdurrahman Elbasir ◽  
Hossam Al Meer ◽  
Sanjay Chawla ◽  
Ehsan Ullah
Keyword(s):  
Clinical Trials ◽  
De Novo ◽  
Drug Repurposing ◽  
Binding Energies ◽  
Protein Activity ◽  
De Novo Drug Design ◽  
Docking Simulations ◽  
Antibiotic Drugs ◽  
Approved Drugs ◽  
Ranked List

<div>Motivation: A global effort is underway to identify drugs for the treatment of COVID-19. Since de novo drug design is an extremely long, time-consuming, and expensive process, efforts are underway to discover existing drugs that can be</div><div>repurposed for COVID-19.</div><div><br></div><div>Model: We propose a machine learning representation framework that uses deep learning induced vector embeddings of drugs and viral proteins as features to predict drug-viral protein activity. The prediction model in-turn is used to build an ensemble framework to rank approved drugs based on their ability to inhibit the three main proteases (enzymes) of the SARS-COV-2 virus.</div><div><br></div><div>Results: We identify a ranked list of 19 drugs as potential targets including 7 antivirals, 6 anticancer, 3 antibiotics, 2 antimalarial, and 1 antifungal. Several drugs, such as Remdesivir, Lopinavir, Ritonavir, and Hydroxychloroquine, in our ranked list, are currently in clinical trials. Moreover, through molecular docking simulations, we demonstrate that majority of the anticancer and antibiotic drugs in our ranked list have low binding energies and thus high binding affinity with the 3CL-pro protease of SARS-COV-2 virus.</div><div><br></div><div>Disclaimer: Our models are computational and the drugs suggested should not be taken for treating COVID-19 without a doctor's advice, as further wet-lab research and clinical trials are essential to elucidate their efficacy for this purpose.</div>

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

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>

scholarly journals Host-directed FDA-approved drugs with antiviral activity against SARS-CoV-2 identified by hierarchical in silico/in vitro screening methods

2020 ◽  
Author(s):  
Tiziana Ginex ◽  
Urtzi Garaigorta ◽  
David Ramírez ◽  
Victoria Castro ◽  
Vanesa Nozal ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
In Silico ◽  
Drug Repurposing ◽  
Screening Methods ◽  
Speed Up ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Virtual Screening Approach

AbstractThe unprecedent situation generated by the COVID-19 global emergency has prompted scientists around the world to actively work to fight against this pandemic. In this sense, it is remarkable the number of drug repurposing efforts trying to shed light into the COVID-19 patients’ treatment.In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way.A successful combination of a multi-target virtual screening approach focused on host-based targets related to viral entry and experimental evaluation of the antiviral activity of selected compounds has been carried out. As a result, three different potentially repurposable drugs interfering with viral entry, cepharantine, imatinib and efloxate, have been identified.

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

2019 ◽  
pp. 625-648 ◽  
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

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

2019 ◽  
Vol 26 (28) ◽  
pp. 5363-5388 ◽  
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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