Genetic Algorithm-Based Docking of Potent Inhibitors Against SARS-CoV-2 Main Protease: A Comparison Between Natural Products and Synthetic Drugs.

Betulinic Acid ◽

Drug Target ◽

Vital Role ◽

Intensive Research ◽

Synthetic Drugs ◽

Main Protease ◽

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused coronavirus disease-2019 (COVID-19) pandemic. Despite the intensive research currently, there are no therapeutics and vaccines available. As the main protease (MPro) plays a vital role in SARS-CoV-2, it is an attractive drug target. Herein we report, potential inhibitors form natural products and synthetic drugs against MPro. In detail, we studied the interaction of inhibitors (Curcumin, Theaflavin, Deserpidine, Betulinic acid, Sinigrin, Emodin, Leptodactylone, Synthetic drugs, Lopinavir, Ritonavir, Indinavir, Amprenavir, Darunavir, Nelfinavir, Remdesivir, Saquinavir, Sivelestat, Galidesivir, and Favipiravir) with the catalytic site of MPro. Lastly, ADME (Absorption, Distribution, Metabolism, and Excretion) properties of Natural products and synthetic drugs are explored. We identified eight potential inhibitors against MPro.

COMPUTATIONAL SCREENING AND MOLECULAR DOCKING OF LICHEN SECONDARY METABOLITES AGAINST SEVERE ACUTE RESPIRATORY SYNDROME-COV-2 MAIN PROTEASE AND SPIKE PROTEIN

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2021.v14i12.43227 ◽

2021 ◽

pp. 100-104

Author(s):

SENTHIL PRABHU S ◽

SATHISHKUMAR R ◽

KIRUTHIKA B

Keyword(s):

Molecular Docking ◽

Study Finding ◽

Spike Protein ◽

Protein Targets ◽

Lipinski’S Rule ◽

Computational Screening ◽

Main Protease ◽

Lichen Compounds ◽

Objective: At present, the coronavirus disease (COVID)-19 pandemic is increasing global health concerns. This coronavirus outbreak is caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2. Since, no specific antiviral for treatment against COVID-19, so identification of new therapeutics is an urgent need. The objective of this study is to the analysis of lichen compounds against main protease and spike protein targets of SARS-CoV-2 using in silico approach. Methods: A total of 108 lichen compounds were subjected to ADMET analysis and 14 compounds were selected based on the ADMET properties and Lipinski’s rule of five. Molecular docking was performed for screening of selected individual lichen metabolites against the main protease and spike proteins of SARS-CoV-2 by Schrodinger Glide module software. Results: Among the lead compounds, fallacinol showed the highest binding energy value of −11.83 kcal/mol against spike protein, 4-O-Demethylbarbatic acid exhibited the highest dock score of −11.67 kcal/mol against main protease. Conclusion: This study finding suggests that lichen substances may be potential inhibitors of SARS-CoV-2.

Computational Estimation of Potential Inhibitors from the Known Drugs against the Main Protease of SARS-CoV-2

10.26434/chemrxiv.14102675.v1 ◽

2021 ◽

Author(s):

Nguyen Minh Tam ◽

Pham Minh Quan ◽

Nguyen Xuan Ha ◽

Pham Cam Nam ◽

Huong Thi Thu Phung

Keyword(s):

Molecular Docking ◽

Potential Application ◽

Drug Database ◽

Computational Estimation ◽

Main Protease ◽

The coronavirus disease (COVID-19) pandemic caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide recently, leading to a global social and economic disruption. Although the emergently approved vaccine programs against SARS-CoV-2 have been rolled out globally, the number of COVID-19 daily cases and deaths has remained significantly high. Here, we attempted to computationally screen for possible medications for COVID-19 via rapidly estimate the highly potential inhibitors from an FDA-approved drug database against the main protease (Mpro) of SARS-CoV-2. The approach combined molecular docking and fast pulling of ligand (FPL) simulations that were demonstrated to be accurate and suitable for quick prediction of SARS-CoV-2 Mpro inhibitors. The results suggested that twentyseven compounds were capable of strongly associating with SARS-CoV-2 Mpro. Among them, the seven top leads are daclatasvir, teniposide, etoposide, levoleucovorin, naldemedine, cabozantinib, and irinotecan. The potential application of these drugs in COVID-19 therapy has thus been discussed.

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 ◽

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.

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

Science ◽

10.1126/science.abb3405 ◽

2020 ◽

Vol 368 (6489) ◽

pp. 409-412 ◽

Cited By ~ 468

Author(s):

Linlin Zhang ◽

Daizong Lin ◽

Xinyuanyuan Sun ◽

Ute Curth ◽

Christian Drosten ◽

...

Keyword(s):

Crystal Structure ◽

Drug Target ◽

Essential Role ◽

Potent Inhibitor ◽

Amide Bond ◽

Lead Compound ◽

X Ray ◽

Main Protease

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

Identification of Potential Inhibitors of Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Main Protease from Non-Natural and Natural Sources: A Molecular Docking Study

Journal of the Brazilian Chemical Society ◽

10.21577/0103-5053.20200139 ◽

2020 ◽

Author(s):

Osvaldo Santos-Filho

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Molecular Docking Study ◽

Natural Sources ◽

Main Protease ◽

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 ◽

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.

Crystal structures of human coronavirus NL63 main protease at different pH values

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x21009523 ◽

2021 ◽

Vol 77 (10) ◽

Author(s):

Hongxia Gao ◽

Yuting Zhang ◽

Haihai Jiang ◽

Xiaohui Hu ◽

Yuting Zhang ◽

...

Keyword(s):

Crystal Structures ◽

Drug Target ◽

Clinical Manifestations ◽

Structural Features ◽

Vital Role ◽

Human Coronavirus ◽

Respiratory Illnesses ◽

Ph Values ◽

Main Protease ◽

Etiological Agents

Human coronavirus NL63 (HCoV-NL63), which belongs to the genus Alphacoronavirus, mainly infects children and the immunocompromized and is responsible for a series of clinical manifestations, including cough, fever, rhinorrhoea, bronchiolitis and croup. HCoV-NL63, which was first isolated from a seven-month-old child in 2004, has led to infections worldwide and accounts for 10% of all respiratory illnesses caused by etiological agents. However, effective antivirals against HCoV-NL63 infection are currently unavailable. The HCoV-NL63 main protease (Mpro), also called 3C-like protease (3CLpro), plays a vital role in mediating viral replication and transcription by catalyzing the cleavage of replicase polyproteins (pp1a and pp1ab) into functional subunits. Moreover, Mpro is highly conserved among all coronaviruses, thus making it a prominent drug target for antiviral therapy. Here, four crystal structures of HCoV-NL63 Mpro in the apo form at different pH values are reported at resolutions of up to 1.78 Å. Comparison with Mpro from other human betacoronaviruses such as SARS-CoV-2 and SARS-CoV reveals common and distinct structural features in different genera and extends knowledge of the diversity, function and evolution of coronaviruses.

Prevention of SARS-CoV-2 Proliferation with a Novel and Potent Main Protease Inhibitor by Docking, ADMET, MM-PBSA, and Molecular Dynamics Simulation

Journal of Computational Biophysics and Chemistry ◽

10.1142/s2737416521500149 ◽

2021 ◽

pp. 2150014

Author(s):

Akbar Noorbakhsh ◽

Rafee Habib Askandar ◽

Mohammad Shakib Alhagh ◽

Chiako Farshadfar ◽

Seyed Hamid Seyedi ◽

...

Keyword(s):

Molecular Dynamics ◽

Drug Target ◽

Md Simulation ◽

Vital Role ◽

Lung Damage ◽

Dynamics Simulation ◽

Reference Drug ◽

Main Protease ◽

Poisson Boltzmann ◽

Adme Properties

COVID-19 is the last disease caused by SARS-CoV-2 associated with a severe immune response and lung damage. The main protease (Mpro) has a vital role in SARS-CoV-2 proliferation. Moreover, humans lack homologous Mpro, which makes the Mpro a suitable drug target for the development of SARS-CoV-2 drugs. The purchasable L5000 library (Selleckchem Inc) includes 99,040 compounds that were used for virtual screening. After molecular docking and ADME studies, we selected a compound (WAY-604395) with a potent binding affinity to the Mpro active site and acceptable ADME properties compared to the reference drug (nelfinavir). Molecular dynamics (MD) simulation outcomes have proved that the Mpro-WAY604395 complex possesses a considerable value of flexibility, stability, compactness and binding energy. Our Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculation demonstrates that WAY-604395 is more potent ([Formula: see text]272.19[Formula: see text]kcal mol[Formula: see text]) in comparison with nelfinavir ([Formula: see text]173.39[Formula: see text]kcal[Formula: see text]mol[Formula: see text]) against SARS-CoV-2 Mpro. In conclusion, we suggest that WAY-604395 has the potential for the treatment of SARS-CoV-2 by inhibition of the Mpro.

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.