An in-silico evaluation of COVID-19 main protease with clinically approved drugs

10.26434/chemrxiv.12318689.v2 ◽

2020 ◽

Author(s):

TACHOUA Wafa ◽

KABRINE Mohamed ◽

Mamona Mushtaq ◽

Zaheer Ul-Haq

Keyword(s):

Conformational Dynamics ◽

Interaction Mechanism ◽

Docking Studies ◽

Binding Affinities ◽

Binding Modes ◽

Wuhan City ◽

Main Protease ◽

Approved Drugs ◽

Potential Inhibitors ◽

Binding Substrate

A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor, we performed blind docking studies on the main virus protease Mpro with eight approved drugs belonging to four pharmacological classes such as: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. When docked against Mpro crystal structure, these two compounds revealed a minimum binding energy of -8.87 and -8.71 kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Further, to study the interaction mechanism and conformational dynamics of protein-ligand complexes, Molecular dynamic simulation and MM/PBSA binding free calculations were performed. Our results showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness properties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like protease (3CLpro) of SARS-CoV-2.

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Microbial Natural Products as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro)

Microorganisms ◽

10.3390/microorganisms8070970 ◽

2020 ◽

Vol 8 (7) ◽

pp. 970 ◽

Cited By ~ 4

Author(s):

Ahmed M. Sayed ◽

Hani A. Alhadrami ◽

Ahmed O. El-Gendy ◽

Yara I. Shamikh ◽

Lassaad Belbahri ◽

...

Keyword(s):

Natural Products ◽

Protein Complexes ◽

Binding Free Energy ◽

Binding Affinities ◽

Binding Modes ◽

Drug Candidates ◽

Main Protease ◽

Potential Inhibitors ◽

Microbial Natural Products

The main protease (Mpro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski’s rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme’s conformers. Final MDS experiments were performed on the ligand–protein complexes (compounds 1–12, Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (1–6) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the Mpro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.

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Molecular Docking Study of COVID-19 Main Protease with Clinically Approved Drugs

10.26434/chemrxiv.12318689.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

TACHOUA Wafa ◽

KABRINE Mohamed

Keyword(s):

Docking Study ◽

Docking Studies ◽

Binding Modes ◽

Molecular Docking Study ◽

In Vivo Evaluation ◽

Binding Cavity ◽

Approved Drugs ◽

Potential Inhibitors

A novel strain of coronavirus, namely, Corona Virus Infection Disease 19 has been identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor we performed docking studies on the main virus protease with eight drugs belonging to four pharmacological classes: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. These two compounds revealed a minimum binding energy of -8.87 and -8.71 Kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Lymecycline and Mizolastine interact with specific residues in substrate binding cavity. Thus, Lymecycline and Mizolastione may serve as a tool to fight COVID-19 disease. However, this data need further in vitro and in vivo evaluation to repurpose these two drugs against COVID-19 disease.

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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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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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Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

10.20944/preprints202004.0062.v1 ◽

2020 ◽

Cited By ~ 4

Author(s):

Vijayakumar Balakrishnan ◽

Karthik Lakshminarayanan

Keyword(s):

Vaccine Development ◽

New Drugs ◽

World Health ◽

Wuhan City ◽

Drug Candidates ◽

Human Contact ◽

Main Protease ◽

Potent Drug ◽

Approved Drugs ◽

Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.

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Azadirachtin-A a bioactive compound from Azadiracta indica is a potential inhibitor of SARS-CoV-2 main protease

10.53858/arocpb01010108 ◽

2021 ◽

Vol 01 (01) ◽

pp. 01-08

Author(s):

Eustace Berinyuy ◽

◽

Jonathan Ibrahim ◽

Blessing Alozieuwa

Keyword(s):

Bioactive Compound ◽

Docking Study ◽

Preclinical Study ◽

Binding Modes ◽

Molecular Docking Study ◽

Potential Inhibitor ◽

Main Protease ◽

Binding Cavity ◽

Approved Drugs ◽

Azadirachtin A

Despite the growing scientific interest in finding effective treatment, SARS-CoV-2 virus remains a global major health burden and public health emergency. SARS-CoV main protease (Mpro) also known as chymotrypsin-like protease (3CLpro) is an important protein identified to be vital for SARS-CoV-2 survival. However, to date, there are no clinically approved drugs or antibodies specific for SARS-CoV-2. In the present study, we evaluated the interaction of 3CLpro with azadirachtin-A a bioactive compound from Azadiracta indica using in silico molecular docking study. Our results revealed that Azadiractin A docked well into the binding cavity of 3CLproSARS-CoV-2 with binding affinities ranges between -6.3 and -5.20 kcal/mol, and Pkd of 5.82~6.10 for the ten best binding modes. Azadiractin interacted with the active site of 3CLpro-SARS-CoV-2 by 2 conventional hydrogen bonding to HIS163 and GLU166, C-H interactions with HIS127, and alkyl interaction with PRO168 of the 3CLpro-SARS-CoV-2. We also found that the Azadiractin-A_3CLpro-SARS-CoV-2 complex is stabilized by various Vander wall forces with ASN142, LEU141, PHE140, MET165, GLN189, LEU167, THR190, and ALA191. In conclusion, our results suggested that Azadirachtin-A could be a potential inhibitor of SARS-CoV-2 main protease, thus worthy of further preclinical study.

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A Potential Peptide From Soy Cheese Produced Using Lactobacillus delbrueckii WS4 for Effective Inhibition of SARS-CoV-2 Main Protease and S1 Glycoprotein

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.601753 ◽

2020 ◽

Vol 7 ◽

Author(s):

Rounak Chourasia ◽

Srichandan Padhi ◽

Loreni Chiring Phukon ◽

Md Minhajul Abedin ◽

Sudhir P. Singh ◽

...

Keyword(s):

Drug Targets ◽

Docking Studies ◽

Lactobacillus Delbrueckii ◽

Amino Acid Residues ◽

Main Protease ◽

Effective Inhibition ◽

Cheese Peptides ◽

Potential Inhibitors

The COVID-19 pandemic caused by novel SARS-CoV-2 has resulted in an unprecedented loss of lives and economy around the world. In this study, search for potential inhibitors against two of the best characterized SARS-CoV-2 drug targets: S1 glycoprotein receptor-binding domain (RBD) and main protease (3CLPro), was carried out using the soy cheese peptides. A total of 1,420 peptides identified from the cheese peptidome produced using Lactobacillus delbrueckii WS4 were screened for antiviral activity by employing the web tools, AVPpred, and meta-iAVP. Molecular docking studies of the selected peptides revealed one potential peptide “KFVPKQPNMIL” that demonstrated strong affinity toward significant amino acid residues responsible for the host cell entry (RBD) and multiplication (3CLpro) of SARS-CoV-2. The peptide was also assessed for its ability to interact with the critical residues of S1 RBD and 3CLpro of other β-coronaviruses. High binding affinity was observed toward critical amino acids of both the targeted proteins in SARS-CoV, MERS-CoV, and HCoV-HKU1. The binding energy of KFVPKQPNMIL against RBD and 3CLpro of the four viruses ranged from −8.45 to −26.8 kcal/mol and −15.22 to −22.85 kcal/mol, respectively. The findings conclude that cheese, produced by using Lb. delbrueckii WS4, could be explored as a prophylactic food for SARS-CoV-2 and related viruses. In addition, the multi-target inhibitor peptide, which effectively inhibited both the viral proteins, could further be used as a terminus a quo for the in vitro and in vivo function against SARS-CoV-2.

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MOLECULAR DOCKING STUDIES ON SCREENING AND ASSESSMENT OF SELECTED BIOFLAVONOIDS AS POTENTIAL INHIBITORS OF COVID-19 MAIN PROTEASE

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2020.v13i9.38485 ◽

2020 ◽

pp. 174-178

Author(s):

SHAILENDRA SANJAY SURYAWANSHI ◽

POOJA BHAVAKANA JAYANNACHE ◽

RAJKUMAR SANJAY PATIL ◽

PALLED MS ◽

ALEGAON SG

Keyword(s):

Molecular Docking ◽

Treatment Options ◽

Docking Studies ◽

Binding Energies ◽

Molecular Docking Studies ◽

Discovery Studio ◽

Main Protease ◽

Potential Inhibitors ◽

Binding Energy Calculations ◽

Native Ligand

Objectives: The objective of the study was to screen and assess the selected bioactive bioflavonoids in medicinal plants as potential coronaviruses (CoV) main protease (Mpro) inhibitors using molecular docking studies. Methods: We have investigated several bioflavonoids which include apigenin, galangin, glycitein, luteolin, morin, naringin, resveratrol, and rutin. Nelfinavir and lopinavir were used as standard antiviral drugs for comparison. Mpro was docked with selected compounds using PyRx 0.8 and docking was analyzed by PyRx 0.8 and Biovia Discovery Studio 2019. Results: The binding energies obtained from the docking of 6LU7 with native ligand, nelfinavir, lopinavir, apigenin, galangin, glycitein, luteolin, morin, naringin, resveratrol, and rutin were found to be −7.4, −8.3, −8.0, −7.8, −7.3, −7, −7.4, −7.6, −7.8, −6.9, and −9 kcal/mol, respectively. Conclusion: From the binding energy calculations, we can conclude that nelfinavir and lopinavir may represent potential treatment options and apigenin, galangin, glycitein, luteolin, morin, naringin, resveratrol, and rutin found to possess the best inhibitors of CoV disease-19 main protease.

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Virtual Screening of Potential Inhibitors for SARS-CoV-2 Main Protease

10.20944/preprints202004.0146.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Carlos Javier Alméciga-Díaz ◽

Luisa N. Pimentel-Vera ◽

Angela Caro ◽

Angela Mosquera ◽

Camilo Andrés Castellanos Moreno ◽

...

Keyword(s):

Virtual Screening ◽

Clinical Information ◽

Virus Genome ◽

Pharmacological Agents ◽

Main Protease ◽

Novel Coronavirus ◽

Approved Drugs ◽

Potential Inhibitors

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (Mpro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 Mpro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 Mpro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 Mpro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

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