Repurposing Simeprevir, Calpain Inhibitor IV and a Cathepsin F Inhibitor Against SARS-CoV-2: A Study Using in Silico Pharmacophore Modeling and Docking Methods

The world has come to a sudden halt due to the incessant spread of a viral pneumonia dubbed COVID-19 caused by the beta-coronavirus, SARS-CoV-2. The pandemic spread of the virus has already claimed lakhs of valuable lives and has infected millions of people across the globe. The situation is further worsened by the fact that there is no approved therapeutics currently available for the treatment of the disease. The only way to handle the crisis is the rapid development of a therapeutic strategy to combat the virus. Computational biology offers resources to rapidly identify novel drug leads and to repurpose existing drugs at the expense of minimal resources and time. The main protease of SARS-CoV-2 is key to the replication and propogation of the virus in the host cells. Inhibiting the protease blocks replication and hence is an attractive therapeutic target in the virus. The crystal structures of the protein in complex with inhibitors are available in public databases. Here we describe the screening of the DrugBank database, a public repository for small molecule therapeutics, to identify approved or experimental phase drugs that can be repurposed against the main protease of SARS-CoV2. The initial screening was performed on more than 13,000 drug entries in the target database using an energy optimised pharmacophore hypothesis AARRR. A sub-set of the molecules selected based on the fitness score was further screened using molecular docking by sequentially filtering the molecules through the high throughput virtual screening, extra precision and standard precision docking modalities. The most promising hits were subjected to binding free energy estimation using the MMGBSA method. Approved drugs viz, Cobicistat, Larotrectinib and Simeprevir were identified as potential candidates for repurposing. Drugs in the discovery phase identified as inhibitors include the known cysteine protease inhibitors, Calpain inhibitor IV and an experimental cathepsin F inhibitor.

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Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

10.26434/chemrxiv.12199610 ◽

2020 ◽

Author(s):

arun kumar ◽

Sharanya C.S ◽

Abhithaj J ◽

Dileep Francis ◽

Sadasivan C

Keyword(s):

Free Energy ◽

Molecular Docking ◽

Drug Target ◽

Binding Free Energy ◽

Drug Repurposing ◽

Energy Calculation ◽

Viral Protease ◽

Energy Estimation ◽

Main Protease ◽

Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

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Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

10.26434/chemrxiv.12199610.v1 ◽

2020 ◽

Author(s):

arun kumar ◽

Sharanya C.S ◽

Abhithaj J ◽

Dileep Francis ◽

Sadasivan C

Keyword(s):

Free Energy ◽

Molecular Docking ◽

Drug Target ◽

Binding Free Energy ◽

Drug Repurposing ◽

Energy Calculation ◽

Viral Protease ◽

Energy Estimation ◽

Main Protease ◽

Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

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A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients

10.26434/chemrxiv.12630539 ◽

2020 ◽

Cited By ~ 1

Author(s):

Dharmendra Kumar Maurya

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Binding Affinity ◽

Viral Entry ◽

Virus Disease ◽

Host Cells ◽

Dynamics Simulation ◽

Host Immune System ◽

Main Protease ◽

Approved Drugs

The current outbreak of the corona virus disease 2019 (COVID-19), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it. Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID-19 patients. To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease (Mpro), Spike (S) protein, Nucleocapsid (N), RNA-dependent RNA polymerase (RdRp, NSP12), ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor. Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system. Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro, Spike, NSP3, NSP16 and ACE2 was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.

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Crystal-Structures-Guided Design of Fragment-Based Drugs for Inhibiting the Main Protease of SARS-CoV-2

10.21203/rs.3.rs-80869/v1 ◽

2020 ◽

Author(s):

Binquan Luan ◽

Tien Huynh

Keyword(s):

Binding Free Energy ◽

Dynamics Simulation ◽

Drug Molecule ◽

Protein Targets ◽

Main Protease ◽

Potent Drug ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Efficacious Drug ◽

Better Than

Abstract Since the beginning of the COVID-19 pandemic, researchers and scientists across the globe are racing to find a cure for the highly contagious infectious disease caused by the SARS-CoV-2 virus. Despite many promising ongoing progress, there are currently no FDA approved drugs to treat infected patients. Among the various protein targets of SARS-CoV-2 virus, the main protease (Mpro) has attracted most interests. Recently, the crowdsourcing of drug discovery for inhibiting Mpro have yielded a plenty of drug fragments resolved inside the active site of Mpro via the crystallography method. Following the principle of fragment-based drug design (FBDD), we are motivated to design a potent drug molecule through merging several of these newly discovered drug fragments. Among various designed ligands, we found that B19 by merging three fragments JFM, U0P and HWH is the most stable one, evidenced through extensive (~10 μs totally) all-atom molecular dynamics simulation. We further estimated that the binding free energy of B19 is comparable or even a little better than that of a native protein ligand processed by Mpro. Our promising results suggest that B19 can potentially be an efficacious drug molecule for inhibiting Mpro of SARS-CoV-2.

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A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 Patients

10.26434/chemrxiv.12630539.v1 ◽

2020 ◽

Author(s):

Dharmendra Kumar Maurya

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Binding Affinity ◽

Viral Entry ◽

Virus Disease ◽

Host Cells ◽

Dynamics Simulation ◽

Host Immune System ◽

Main Protease ◽

Approved Drugs

The current outbreak of the corona virus disease 2019 (COVID-19), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it. Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID-19 patients. To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease (Mpro), Spike (S) protein, Nucleocapsid (N), RNA-dependent RNA polymerase (RdRp, NSP12), ADP Ribose Phosphatase (NSP3), Endoribonuclease (NSP15) and methyltransferase (NSP10-NSP16 complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor. Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 interacting region indicating that it might be interfering in the interaction of spike with ACE2 and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3, NSP10, NSP15 and NSP16 which helps virus in escaping from host immune system. Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro, Spike, NSP3, NSP16 and ACE2 was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.

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Repurposing of FDA-approved Drugs against Active Site and Potential Allosteric Drug Binding Sites of COVID-19 Main Protease

10.22541/au.161841491.18932381/v1 ◽

2021 ◽

Author(s):

Merve Yuce ◽

Erdem Cicek ◽

Tuğçe İnan ◽

Aslıhan Başak Dağ ◽

Özge Kürkçüoğlu ◽

...

Keyword(s):

Active Site ◽

Social Life ◽

Binding Free Energy ◽

Antiviral Drug ◽

Drug Binding ◽

Allosteric Site ◽

Main Protease ◽

Allosteric Sites ◽

Approved Drugs ◽

Fda Approved Drugs

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, FDA-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. 14 best molecule hits for the active site of Mpro are determined. 6 of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and -42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infection

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Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

10.26434/chemrxiv.13032578 ◽

2020 ◽

Author(s):

Gagandeep Singh ◽

vishal srivastava ◽

Ritpratik Mishra ◽

Gaurav Goel ◽

Tapan Chaudhuri

Keyword(s):

Drug Design ◽

Binding Free Energy ◽

Md Simulations ◽

Docking Studies ◽

Free Energy Calculations ◽

World Health ◽

Main Protease ◽

Health Organization ◽

Approved Drugs ◽

Potential Inhibitors

In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1st October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (Mpro) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of Mpro, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened Mpro inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.

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Potential inhibitors of protease 3CLpro virus COVID-19: drug reposition

Biomedical Chemistry Research and Methods ◽

10.18097/bmcrm00124 ◽

2020 ◽

Vol 3 (1) ◽

pp. e00124

Author(s):

V.S. Skvortsov ◽

D.S. Druzhilovskiy ◽

A.V. Veselovsky

Keyword(s):

Drug Development ◽

Kinase Inhibitor ◽

Experimental Testing ◽

Docking Simulation ◽

Hiv Protease ◽

Energy Estimation ◽

Main Protease ◽

Drug Reposition ◽

Approved Drugs ◽

Potential Inhibitors

Pneumonia caused by the COVID-19 virus has led to quick search of drugs that would able to block the spread of this virus. A standard way of drug development is a long process. One approach that can significantly accelerate drug development is drug reposition. In this study a virtual screening of the database of approved drugs has been used for search inhibitors against 3СLpro COVID-19, the main protease of COVID-19. Molecular docking, simulation of molecular dynamics and binding energy estimation by MM-GBSA method allowed to select several compounds for further experimental testing. The most promising drugs are the HIV protease inhibitor Indinavir, the inhibitor of protease hepatitis C Telaprevir, the antiulcer drug Dalargin, and the ErB receptor tyrosine kinase inhibitor Neratinib

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Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

10.26434/chemrxiv.13032578.v1 ◽

2020 ◽

Author(s):

Gagandeep Singh ◽

vishal srivastava ◽

Ritpratik Mishra ◽

Gaurav Goel ◽

Tapan Chaudhuri

Keyword(s):

Drug Design ◽

Binding Free Energy ◽

Md Simulations ◽

Docking Studies ◽

Free Energy Calculations ◽

World Health ◽

Main Protease ◽

Health Organization ◽

Approved Drugs ◽

Potential Inhibitors

In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1st October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (Mpro) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of Mpro, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened Mpro inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.

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