Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

Rapid Development ◽

Economic Loss ◽

Binding Pocket ◽

Natural Compounds ◽

Active Site Residues ◽

Reference Drug ◽

Drug Molecules ◽

Recently, the emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. In the fight against COVID-19, the rapid development of new drug molecules is the need of hour. However, the conventional approaches of drug development is time consuming and expensive in nature. In this study, we have adopted an alternative approach to identify lead molecules from natural sources using high throughput virtual screening approach. Ligands from natural compounds library from Selleck Inc (L1400) have been screened to evaluate their ability to bind and inhibit the main protease (Mpro or 3CLpro) of SARS-CoV-2, which is a potential drug target. We found that Kaempferol, Quercetin, and Rutin were able to bind at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin was much higher than Chloroquine (1000 times) and Hydroxychloroquine (100 times) and was comparable to that of the reference drug Remdesivir, which is in clinical trials to treat COVID-19 patients. The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.

Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

10.26434/chemrxiv.12362333 ◽

2020 ◽

Author(s):

Md Tabish Rehman ◽

Mohamed F AlAjmi ◽

Afzal Hussain

Keyword(s):

Clinical Trials ◽

Rapid Development ◽

Economic Loss ◽

Binding Pocket ◽

Natural Compounds ◽

Active Site Residues ◽

Reference Drug ◽

Drug Molecules ◽

Recently, the emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. In the fight against COVID-19, the rapid development of new drug molecules is the need of hour. However, the conventional approaches of drug development is time consuming and expensive in nature. In this study, we have adopted an alternative approach to identify lead molecules from natural sources using high throughput virtual screening approach. Ligands from natural compounds library from Selleck Inc (L1400) have been screened to evaluate their ability to bind and inhibit the main protease (Mpro or 3CLpro) of SARS-CoV-2, which is a potential drug target. We found that Kaempferol, Quercetin, and Rutin were able to bind at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin was much higher than Chloroquine (1000 times) and Hydroxychloroquine (100 times) and was comparable to that of the reference drug Remdesivir, which is in clinical trials to treat COVID-19 patients. The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.

Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

Current Pharmaceutical Design ◽

10.2174/1381612826999201116195851 ◽

2020 ◽

Vol 26 ◽

Author(s):

Md Tabish Rehman ◽

Mohamed F. AlAjmi ◽

Afzal Hussain

Keyword(s):

Rapid Development ◽

Economic Loss ◽

Binding Pocket ◽

Natural Compounds ◽

Active Site Residues ◽

Substrate Binding Pocket ◽

Reference Drug ◽

Drug Molecules ◽

Abstract:: The emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. Rapid development of new drug molecules is the need of hour to fight COVID-19. However, the conventional approaches of drug development are time consuming and expensive. Here, we have adopted a computational approach to identify lead molecules from nature. Ligands from natural compounds library available at Selleck Inc (L1400) have been screened for their ability to bind and inhibit the main protease (3CLpro) of SARS-CoV-2. We found that Kaempferol, Quercetin, and Rutin were bound at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin (~106 M-1) was much higher than Chloroquine (~103 M-1) and Hydroxychloroquine (~104 M-1), and the reference drug Remdesivir (~105 M-1). The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable/higher potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.

Identification of Natural Compounds (Proanthocyanidin and Rhapontin) as High-Affinity Inhibitor of SARS-CoV-2 Mpro and PLpro using Computational Strategies

Archives of Medical Science ◽

10.5114/aoms/133706 ◽

2021 ◽

Author(s):

Mohamed AlAjmi ◽

Asim Azhar ◽

Sadaf Hasan ◽

Abdullah Alshabr ◽

Afzal Hussain ◽

...

Keyword(s):

Economic Loss ◽

Natural Compounds ◽

Free Energy Calculations ◽

Dynamics Simulation ◽

In Vivo Studies ◽

Protein Inhibitor ◽

Active Site Residues

IntroductionThe emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic loss. Amongst many proteins encoded by SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and Papain-like protease (PLpro) serve as an attractive drug target.Material and methodsWe screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). 50 top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal mol-1 against Mpro and ≤ -5.0 kcal mol-1 against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes.ResultsProanthocyanidin and Rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while Rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of Proanthocyanidin and Rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol.ConclusionsThis study's outcome may serve Proanthocyanidin and Rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validations by in vitro and in vivo studies.

Computational Studies to Identify Potential Main Protease Inhibitors for SARS-CoV-2

10.26434/chemrxiv.12593765.v2 ◽

2020 ◽

Author(s):

M. Elizabeth Sobhia ◽

Ketan Ghosh ◽

Srikanth Sivangula ◽

Harmanpreet Singh ◽

Siva Kumar

Keyword(s):

In Silico ◽

Experimental Studies ◽

Binding Pocket ◽

Vital Role ◽

Active Site Residues ◽

X Ray Diffraction ◽

Main Protease ◽

Docking Protocol ◽

In Silico Studies

The Coronavirus pandemic has put the entire humanity in total shock and has forced the world to go under total lockdown. It is time for the entire scientific community across the globe to find a solution for this deadly and unseen enemy. In silico studies play a vital role in situations like this, as experimental studies are not feasible by all researchers particularly with relevance to BSL4 procedures. In this study, using the high resolution crystal structure of SARS-CoV-2 main protease (PDB: 5R82), we have identified molecules which can potentially inhibit the main protease (Mpro). We used a three-tier docking protocol making use of three different databases. We analysed the residues which are lying near the ligand binding pocket of the main protease structure and it shows a wide cavity, which can accommodate chemically diverse ligands, occupying different sub-pockets. Using the small fragment bound in the 5R82, we have identified several larger molecules whose functional groups make interactions with the active site residues covering. This study also presumably steers the structure determination of many ligand-main protease complexes using x- ray diffraction methods. These molecules can be used as ‘in silico leads’ and further be explored in the development of SARS-CoV-2 drugs.

Computational Studies to Identify Potential Main Protease Inhibitors for SARS-CoV-2

10.26434/chemrxiv.12593765 ◽

2020 ◽

Author(s):

M. Elizabeth Sobhia ◽

Ketan Ghosh ◽

Srikanth Sivangula ◽

Harmanpreet Singh ◽

Siva Kumar

Keyword(s):

In Silico ◽

Experimental Studies ◽

Binding Pocket ◽

Vital Role ◽

Active Site Residues ◽

X Ray Diffraction ◽

Main Protease ◽

Docking Protocol ◽

In Silico Studies

The Coronavirus pandemic has put the entire humanity in total shock and has forced the world to go under total lockdown. It is time for the entire scientific community across the globe to find a solution for this deadly and unseen enemy. In silico studies play a vital role in situations like this, as experimental studies are not feasible by all researchers particularly with relevance to BSL4 procedures. In this study, using the high resolution crystal structure of SARS-CoV-2 main protease (PDB: 5R82), we have identified molecules which can potentially inhibit the main protease (Mpro). We used a three-tier docking protocol making use of three different databases. We analysed the residues which are lying near the ligand binding pocket of the main protease structure and it shows a wide cavity, which can accommodate chemically diverse ligands, occupying different sub-pockets. Using the small fragment bound in the 5R82, we have identified several larger molecules whose functional groups make interactions with the active site residues covering. This study also presumably steers the structure determination of many ligand-main protease complexes using x- ray diffraction methods. These molecules can be used as ‘in silico leads’ and further be explored in the development of SARS-CoV-2 drugs.

Virtual Screening of Plant-Derived Compounds Against SARS-CoV-2 Viral Proteins Using Computational Tools

10.26434/chemrxiv.13118117 ◽

2020 ◽

Author(s):

Maria Antonela Zigolo ◽

Matías Rivero Goytia ◽

Hugo Ramiro Poma ◽

Verónica Rajal ◽

Veronica Patricia Irazusta

Keyword(s):

Viral Proteins ◽

Natural Compounds ◽

Docking Studies ◽

Binding Energies ◽

Host Cells ◽

Computational Tools ◽

S Protein ◽

Synthetic Drugs ◽

The new SARS-CoV-2, responsible for the COVID-19 pandemic, has been threatening public health worldwide for half a year. The aim of this work was to evaluate compounds of natural origin, mainly from medicinal plants, as potential SARS-CoV-2 inhibitors through docking studies. The viral spike (S) glycoprotein and the main protease Mpro, involved in the recognition of virus by host cells and in viral replication, respectively, were the main molecular targets in this study. The best energy binding values for S protein were, in kcal/mol: -19.22 for glycyrrhizin, -17.84 for gitoxin, -12.05 for dicumarol, -10.75 for diosgenin, and -8.12 for delphinidin. For Mpro were, in kcal/mol: -9.36 for spirostan, -8.75 for N-(3-acetylglycyrrhetinoyl)-2-amino-propanol, -8.41 for α-amyrin, -8.35 for oleanane, -8.11 for taraxasterol, and -8.03 for glycyrrhetinic acid. In addition, the synthetic drugs umifenovir, chloroquine, and hydroxychloroquine were used as controls for S protein, while atazanavir and nelfinavir were used for Mpro. Key hydrogen bonds and hydrophobic interactions between natural compounds and the respective viral proteins were identified, allowing us to explain the great affinity obtained in those compounds with the lowest binding energies. These results suggest that these natural compounds could potentially be useful as drugs to be experimentally evaluated against COVID-19.

Natural Compounds Activities against SARS-CoV-2 Mpro through Bioinformatics Approaches for Development of Antivirus Candidates

Jurnal Kimia Sains dan Aplikasi ◽

10.14710/jksa.24.5.170-176 ◽

2021 ◽

Vol 24 (5) ◽

pp. 170-176

Author(s):

Taufik Muhammad Fakih

Keyword(s):

Binding Free Energy ◽

Natural Compounds ◽

Protein Docking ◽

Ligand Docking ◽

Angiotensin Converting Enzyme 2 ◽

Docking Simulations ◽

Main Protease ◽

Alternative Approach ◽

Therapeutic Mechanism ◽

Almost All

Coronavirus infection (COVID-19) caused by SARS-CoV-2 appears as a pandemic that has spread to almost all countries in the world. Antiviral therapy using natural compounds is one alternative approach to overcome this infectious disease. The therapeutic mechanism is proven effective against the main protease (Mpro) of SARS-CoV-2. This research aims to perform bioinformatics studies, including ligand-docking simulations and protein-protein docking simulations, to identify, evaluate, and explore five compounds' activity on SARS-CoV-2 Mpro and their effects against Angiotensin-Converting Enzyme 2 (ACE-2). Protein-ligand docking simulations show kaempferol, flavonol, and their glycosides (Afzelin and Juglanin) and other flavonoids (Quercetin, Naringenin, and Genistein) have a high affinity towards SARS-CoV-2 Mpro. These results were then confirmed using protein-protein docking simulations to observe the ability of five compounds to prevent the attachment of ACE-2 to the active site. Based on the results of the bioinformatics studies, Quercetin has the best affinity, with a binding free energy value of −33.18 kJ/mol. The five compounds are predicted to be able to interact strongly with SARS-CoV-2. The results in this research are useful for further studies in the development of novel anti-infective drugs for COVID-19 that target SARS-CoV-2 Mpro.

Computational Studies to Identify Potential Main Protease Inhibitors for SARS-CoV-19

10.26434/chemrxiv.12593765.v1 ◽

2020 ◽

Author(s):

M. Elizabeth Sobhia ◽

Ketan Ghosh ◽

Srikanth Sivangula ◽

siva kumar ◽

Harmanpreet Singh

Keyword(s):

In Silico ◽

Experimental Studies ◽

Binding Pocket ◽

Vital Role ◽

Active Site Residues ◽

X Ray Diffraction ◽

Main Protease ◽

Docking Protocol ◽

In Silico Studies

The Coronavirus pandemic has put the entire humanity in total shock and has forced the world to go under total lockdown. It is time for the entire scientific community across the globe to find a solution for this deadly and unseen enemy. In silico studies play a vital role in situations like this, as experimental studies are not feasible by all researchers particularly with relevance to BSL4 procedures. In this study, using the high resolution crystal structure of SARS-CoV-2 main protease (PDB: 5R82), we have identified molecules which can potentially inhibit the main protease (Mpro). We used a three-tier docking protocol making use of three different databases. We analysed the residues which are lying near the ligand binding pocket of the main protease structure and it shows a wide cavity, which can accommodate chemically diverse ligands, occupying different sub-pockets. Using the small fragment bound in the 5R82, we have identified several larger molecules whose functional groups make interactions with the active site residues covering. This study also presumably steers the structure determination of many ligand-main protease complexes using x- ray diffraction methods. These molecules can be used as ‘in silico leads’ and further be explored in the development of SARS-CoV-2 drugs.

Virtual Screening of Plant-Derived Compounds Against SARS-CoV-2 Viral Proteins Using Computational Tools

10.26434/chemrxiv.13118117.v1 ◽

2020 ◽

Author(s):

Maria Antonela Zigolo ◽

Matías Rivero Goytia ◽

Hugo Ramiro Poma ◽

Verónica Rajal ◽

Veronica Patricia Irazusta

Keyword(s):

Viral Proteins ◽

Natural Compounds ◽

Docking Studies ◽

Binding Energies ◽

Host Cells ◽

Computational Tools ◽

S Protein ◽

Synthetic Drugs ◽

The new SARS-CoV-2, responsible for the COVID-19 pandemic, has been threatening public health worldwide for half a year. The aim of this work was to evaluate compounds of natural origin, mainly from medicinal plants, as potential SARS-CoV-2 inhibitors through docking studies. The viral spike (S) glycoprotein and the main protease Mpro, involved in the recognition of virus by host cells and in viral replication, respectively, were the main molecular targets in this study. The best energy binding values for S protein were, in kcal/mol: -19.22 for glycyrrhizin, -17.84 for gitoxin, -12.05 for dicumarol, -10.75 for diosgenin, and -8.12 for delphinidin. For Mpro were, in kcal/mol: -9.36 for spirostan, -8.75 for N-(3-acetylglycyrrhetinoyl)-2-amino-propanol, -8.41 for α-amyrin, -8.35 for oleanane, -8.11 for taraxasterol, and -8.03 for glycyrrhetinic acid. In addition, the synthetic drugs umifenovir, chloroquine, and hydroxychloroquine were used as controls for S protein, while atazanavir and nelfinavir were used for Mpro. Key hydrogen bonds and hydrophobic interactions between natural compounds and the respective viral proteins were identified, allowing us to explain the great affinity obtained in those compounds with the lowest binding energies. These results suggest that these natural compounds could potentially be useful as drugs to be experimentally evaluated against COVID-19.