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

2020 ◽  
Vol 26 ◽  
Author(s):  
Md Tabish Rehman ◽  
Mohamed F. AlAjmi ◽  
Afzal Hussain
Keyword(s):  
Hydrophobic Interactions ◽  
Rapid Development ◽  
Economic Loss ◽  
Binding Pocket ◽  
Natural Compounds ◽  
Active Site Residues ◽  
Substrate Binding Pocket ◽  
Reference Drug ◽  
Drug Molecules ◽  
Main Protease

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.

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

2020 ◽  
Author(s):  
Md Tabish Rehman ◽  
Mohamed F AlAjmi ◽  
Afzal Hussain
Keyword(s):  
Clinical Trials ◽  
Hydrophobic Interactions ◽  
Rapid Development ◽  
Economic Loss ◽  
Binding Pocket ◽  
Natural Compounds ◽  
Active Site Residues ◽  
Reference Drug ◽  
Drug Molecules ◽  
Main Protease

<p></p><p>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 (M<sup>pro</sup> or 3CL<sup>pro</sup>) 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 3CL<sup>pro</sup> with high affinity (10<sup>5</sup>-10<sup>6</sup> M<sup>-1</sup>) 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.</p><br><p></p>

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

2020 ◽  
Author(s):  
Md Tabish Rehman ◽  
Mohamed F AlAjmi ◽  
Afzal Hussain
Keyword(s):  
Hydrophobic Interactions ◽  
Rapid Development ◽  
Economic Loss ◽  
Binding Pocket ◽  
Natural Compounds ◽  
Active Site Residues ◽  
Reference Drug ◽  
Drug Molecules ◽  
Main Protease ◽  
Alternative Approach

<p>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 costly 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 (M<sup>pro</sup> or 3CL<sup>pro</sup>) 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 3CL<sup>pro</sup> with high affinity (10<sup>5</sup>-10<sup>6</sup> M<sup>-1</sup>) 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 the potential of natural compounds (flavonoids) as novel inhibitors of SARS-CoV-2 with comparable potency as that of Remdesivir.</p>

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

2020 ◽  
Author(s):  
Md Tabish Rehman ◽  
Mohamed F AlAjmi ◽  
Afzal Hussain
Keyword(s):  
Clinical Trials ◽  
Hydrophobic Interactions ◽  
Rapid Development ◽  
Economic Loss ◽  
Binding Pocket ◽  
Natural Compounds ◽  
Active Site Residues ◽  
Reference Drug ◽  
Drug Molecules ◽  
Main Protease

<p></p><p>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 (M<sup>pro</sup> or 3CL<sup>pro</sup>) 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 3CL<sup>pro</sup> with high affinity (10<sup>5</sup>-10<sup>6</sup> M<sup>-1</sup>) 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.</p><br><p></p>

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

2021 ◽  
Author(s):  
Mohamed AlAjmi ◽  
Asim Azhar ◽  
Sadaf Hasan ◽  
Abdullah Alshabr ◽  
Afzal Hussain ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
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.

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

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.

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

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.

scholarly journals Possible SARS-coronavirus 2 inhibitor revealed by simulated molecular docking to viral main protease and host toll-like receptor

2020 ◽  
Vol 15 (6) ◽  
pp. 359-368 ◽  
Author(s):  
Xiaopeng Hu ◽  
Xin Cai ◽  
Xun Song ◽  
Chenyang Li ◽  
Jia Zhao ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Protein Assembly ◽  
Metabolic Process ◽  
Toll Like Receptor ◽  
Sars Coronavirus ◽  
Functional Protein ◽  
Substrate Binding Pocket ◽  
Main Protease ◽  
Protein Pockets ◽  
Potential Inhibitors

Aim: SARS-coronavirus 2 main protease (Mpro) and host toll-like receptors (TLRs) were targeted to screen potential inhibitors among traditional antiviral medicinal plants. Materials & methods: LeDock software was adopted to determine the binding energy between candidate molecules and selected protein pockets. Enrichment analyses were applied to illustrate potential pharmacology networks of active molecules. Results: The citrus flavonoid rutin was identified to fit snugly into the Mpro substrate-binding pocket and to present a strong interaction with TLRs TLR2, TLR6 and TLR7. One-carbon metabolic process and nitrogen metabolism ranked high as potential targets toward rutin. Conclusion: Rutin may influence viral functional protein assembly and host inflammatory suppression. Its affinity for Mpro and TLRs render rutin a potential novel therapeutic anti-coronavirus strategy.

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

2020 ◽  
Author(s):  
Maria Antonela Zigolo ◽  
Matías Rivero Goytia ◽  
Hugo Ramiro Poma ◽  
Verónica Rajal ◽  
Veronica Patricia Irazusta
Keyword(s):  
Hydrophobic Interactions ◽  
Viral Proteins ◽  
Natural Compounds ◽  
Docking Studies ◽  
Binding Energies ◽  
Host Cells ◽  
Computational Tools ◽  
S Protein ◽  
Synthetic Drugs ◽  
Main Protease

<p>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 M<sup>pro</sup>, involved in the recognition of virus by host cells and in viral replication, respectively, were the main molecular targets in this study. </p> <p>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 M<sup>pro</sup> were, in kcal/mol: -9.36 for spirostan, -8.75 for <i>N</i>-(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 M<sup>pro</sup>. 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. </p>

scholarly journals High-throughput Screening and Experimental Identification of Potent Drugs Targeting SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Yan Li ◽  
Jinyong Zhang ◽  
Ning Wang ◽  
Yanjing Zhang ◽  
Yongjun Yang ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Binding Pocket ◽  
Substrate Binding Pocket ◽  
Stable Conformation ◽  
Cross Docking ◽  
Main Protease ◽  
Computer Based ◽  
Old Drugs

Abstract The main protease (Mpro) is one of the best-characterized drug targets among coronaviruses. In the current study, we adopted a multiple cross-docking strategy against different crystal structures of SARS-CoV-2 Mpro to perform computer-based high-throughput virtual screening of possible inhibitors from a drug database using Autodock Vina and SeeSAR software, combined with our in-house automatic processing scripts. The KDs between screened candidates and Mpro were determined using Biacore. Seven drugs were found to fit the substrate-binding pocket of Mpro with a stable conformation, showing high KDs that ranged from 6.79E-7 M to 5.20E-5 M. Finally, mutagenesis studies confirmed that these drugs interact with Mpro specifically, suggesting that our method was reliable and convincing. Given the safety of these old drugs, they may serve as promising candidates to treat the infection of SARS-CoV-2. Our results also provide rational explanations for the behaviour of five drugs evaluated in clinical trials.

scholarly journals Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

2014 ◽  
Vol 70 (2) ◽  
pp. 290-298 ◽  
Author(s):  
Benoît Sanson ◽  
Tao Wang ◽  
Jing Sun ◽  
Liqun Wang ◽  
Martin Kaczocha ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Hydrogen Bond ◽  
Hydrophobic Interactions ◽  
Binding Pocket ◽  
Fatty Acid Binding Proteins ◽  
Psychological Processes ◽  
Substrate Binding Pocket ◽  
Fatty Acid Binding ◽  
Crystallographic Study ◽  
Arachidonic Acid Derivatives

In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocketviahydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels.

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