In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy

Abstract COVID-19 has globally spread and has become a new pandemic, but there is still no effective drugs or vaccines to treat or prevent this disease. SARS-Cov-2 invades human cells through its spike proteins interacting with human ACE2 receptors. One strategy to prevent the virus from entering cells is the interruption of the viral spike protein interacting with ACE2. In such an emergent situation, drug repurposing is a promising method for rapid drug development. Here, we selected around 15000 molecular candidates including FDA-approved drugs from DrugBank and natural compounds from TCMSP to perform virtual screening for potential molecules that can target viral spike protein based on its crystal structure. In this article, we present the top 20 molecules with high binding affinity with spike protein, of which, digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP, extracted from indigo naturalis and polygoni tinctorii foliu, have the highest docking scores. In addition, we also found that raltegravir, an HIV integrase inhibitor, has a relatively high binding score. Those molecules with high binding capacity to spike glycoprotein might be used by other researchers for further anti-COVID-19 drug development.

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In silico drug repurposing of anticancer drug 5-FU and analogues against SARS-CoV-2 main protease

10.26434/chemrxiv-2021-gk1gt ◽

2021 ◽

Author(s):

Aristote Matondo ◽

Washington Dendera ◽

Bienfait K. Isamura ◽

Koto-te-Nyiwa Ngbolua ◽

Hilaire V.S. Mambo ◽

...

Keyword(s):

Drug Repurposing ◽

Pharmacological Action ◽

Time Saving ◽

Therapeutic Uses ◽

Main Protease ◽

Approved Drugs ◽

Effective Drugs ◽

Therapeutic Profile

The pressing need to find effective drugs against the current deadly COVID-19 disease has recently motivated numerous studies using different approaches to address the problem. One time-saving and less costly strategy is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same trend, this study has investigated the potential inhibitory activity of 5-FU and its analogues against the SARS-CoV-2 main protease as well as their profile of druggability using molecular docking and ADMET methods. From the calculations performed, four candidates showed promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. Further in-vitro and in-vivo investigations are needed that may clarify their possible mechanism of the pharmacological action to combat COVID-19.

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

10.21203/rs.3.rs-24586/v1 ◽

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.

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In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy

Chinese Journal of Integrative Medicine ◽

10.1007/s11655-020-3427-6 ◽

2020 ◽

Vol 26 (9) ◽

pp. 663-669 ◽

Cited By ~ 3

Author(s):

Tian-zi Wei ◽

Hao Wang ◽

Xue-qing Wu ◽

Yi Lu ◽

Sheng-hui Guan ◽

...

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Spike Glycoprotein ◽

In Silico Screening ◽

Potential Spike ◽

Glycoprotein Inhibitors

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Superiority of cilostazol among antiplatelet FDA ‐approved drugs against COVID 19 M pro and spike protein: Drug repurposing approach

Drug Development Research ◽

10.1002/ddr.21743 ◽

2020 ◽

Author(s):

Mohammed A. Abosheasha ◽

Afnan H. El‐Gowily

Keyword(s):

Drug Repurposing ◽

Spike Protein ◽

Protein Drug ◽

Approved Drugs ◽

Fda Approved Drugs

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Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2

10.26434/chemrxiv.12292514 ◽

2020 ◽

Author(s):

Vaishali Chandel ◽

Prem Prakash Sharma ◽

Sibin Raj ◽

Brijesh Rathi ◽

Dhruv Kumar

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Binding Energy ◽

Active Site ◽

Hydrophobic Interactions ◽

Drug Repurposing ◽

Spike Protein ◽

Structural Protein ◽

Maximum Stability ◽

Spike Proteins

Due to unavailability of therapeutic approach for the novel coronavirus disease (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, in vitro and in vivo validation of these findings will be helpful in bringing these molecules at the clinical settings.

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Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2

10.26434/chemrxiv.12292514.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Vaishali Chandel ◽

Prem Prakash Sharma ◽

Sibin Raj ◽

Brijesh Rathi ◽

Dhruv Kumar

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Binding Energy ◽

Active Site ◽

Hydrophobic Interactions ◽

Drug Repurposing ◽

Spike Protein ◽

Structural Protein ◽

Maximum Stability ◽

Spike Proteins

Due to unavailability of therapeutic approach for the novel coronavirus disease (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, in vitro and in vivo validation of these findings will be helpful in bringing these molecules at the clinical settings.

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Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

International Journal of Molecular Sciences ◽

10.3390/ijms21144957 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4957 ◽

Cited By ~ 1

Author(s):

Federica Laudisi ◽

Martin Marônek ◽

Antonio Di Grazia ◽

Giovanni Monteleone ◽

Carmine Stolfi

Keyword(s):

Digestive System ◽

Drug Repositioning ◽

Drug Repurposing ◽

The Body ◽

Attrition Rates ◽

Anti Cancer ◽

Approved Drugs ◽

Parasitic Worms ◽

Effective Drugs ◽

Anthelmintic Drugs

Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics—a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine—have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.

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

10.21203/rs.3.rs-24586/v2 ◽

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.

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Sitagliptin: a potential drug for the treatment of SARS-CoV-2?

10.31222/osf.io/78mbt ◽

2020 ◽

Author(s):

Sanaa Bardaweel

Keyword(s):

Clinical Trials ◽

Drug Discovery ◽

Antimalarial Drug ◽

Drug Repurposing ◽

Spike Protein ◽

Diabetic Patients ◽

Potential Drug ◽

Chemokine Production ◽

Drug Discovery And Development ◽

Sequence Identity

Recently, an outbreak of fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. As the coronavirus pandemic rages, drug discovery and development become even more challenging. Drug repurposing of the antimalarial drug chloroquine and its hydroxylated form had demonstrated apparent effectiveness in the treatment of COVID-19 associated pneumonia in clinical trials. SARS-CoV-2 spike protein shares 31.9% sequence identity with the spike protein presents in the Middle East Respiratory Syndrome Corona Virus (MERS-CoV), which infects cells through the interaction of its spike protein with the DPP4 receptor found on macrophages. Sitagliptin, a DPP4 inhibitor, that is known for its antidiabetic, immunoregulatory, anti-inflammatory, and beneficial cardiometabolic effects has been shown to reverse macrophage responses in MERS-CoV infection and reduce CXCL10 chemokine production in AIDS patients. We suggest that Sitagliptin may be beneficial alternative for the treatment of COVID-19 disease especially in diabetic patients and patients with preexisting cardiovascular conditions who are already at higher risk of COVID-19 infection.

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