In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

2020 ◽  
Author(s):  
Sahar Qazi ◽  
Mustafa Alhaji Isa ◽  
Adam Mustapha ◽  
Khalid Raza ◽  
Ibrahim Alkali Allamin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
Anacardium Occidentale ◽  
Upper Respiratory Tract ◽  
Ligand Complex ◽  
In Silico Docking ◽  
Main Protease

<p>The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of <i>Zingiber offinale</i> and <i>Anacardium occidentale</i> using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of <i>Zingiber offinale </i>and the leaves of <i>Anacardium occidentale. </i>These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), <i>Pan</i>-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907). </p>

In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

2020 ◽  
Author(s):  
Sahar Qazi ◽  
Mustafa Alhaji Isa ◽  
Adam Mustapha ◽  
Khalid Raza ◽  
Ibrahim Alkali Allamin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Severe Acute Respiratory Syndrome ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
Anacardium Occidentale ◽  
Upper Respiratory Tract ◽  
Ligand Complex ◽  
In Silico Docking ◽  
Main Protease

<p>The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of <i>Zingiber offinale</i> and <i>Anacardium occidentale</i> using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of <i>Zingiber offinale </i>and the leaves of <i>Anacardium occidentale. </i>These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), <i>Pan</i>-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907). </p>

scholarly journals Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

2021 ◽  
Vol 22 (6) ◽  
pp. 2977
Author(s):  
Ahmed Abdelaal Ahmed Mahmoud M. Alkhatip ◽  
Michail Georgakis ◽  
Lucio R. Montero Valenzuela ◽  
Mohamed Hamza ◽  
Ehab Farag ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Study ◽  
Docking Studies ◽  
Binding Energies ◽  
Spike Protein ◽  
Molecular Docking Study ◽  
In Silico Docking ◽  
Main Protease ◽  
Binding Pockets

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at −8.3 kcal/mol, followed by Zn and Ca at −8.0 kcal/mol, and Fe and Mg at −7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn–Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.

scholarly journals in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Muhammad M Ibrahim
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Molecular Dynamic ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
In Silico Docking ◽  
Pharmacokinetic Properties

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in <i>Mycobacterium tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

Screening of Potent Inhibitors Against 2019 Novel Coronavirus (Covid-19) from Alliumsativum and Allium cepa: An In Silico Approach

2020 ◽  
Vol 11 (1) ◽  
pp. 7981-7993
Keyword(s):  
Molecular Docking ◽  
Allium Cepa ◽  
In Silico ◽  
Treatment Options ◽  
Natural Compounds ◽  
Binding Energies ◽  
Drug Candidate ◽  
Molecular Docking Study ◽  
Standard Drug ◽  
Main Protease

The infection of the global COVID-19 pandemic and the absence of any possible treatment options warrants the use of all available resources to find effective drugs against this scourge. Various ongoing researches have been searching for the new drug candidate against COVID-19 infection. The research objective is based on the molecular docking study of inhibition of the main protease of COVID-19 by natural compounds found in Allium sativum and Allium cepa. Lipinski rule of five and Autodock 4.2 was used by using the Lamarckian Genetic Algorithm to perform Molecular docking to analyze the probability of docking. Further, ADME analysis was also performed by using SwissADME, which is freely available on the web. In the present study, we identified S-Allylcysteine sulfoxide (Alliin), S-Propyl cysteine, S-Allylcysteine, S-Ethylcysteine, S-Allylmercaptocysteine, S-Methylcysteine, S-propyl L-cysteine with binding energies (-5.24, -4.49, -4.99, -4.91, -4.79, -4.76, -5.0 kcal/mol) as potential inhibitor candidates for COVID-19. Out of 7 selected compounds, alliin showed the best binding efficacy with target protein 6LU7. In silico ADME analysis revealed that these compounds are expected to have a standard drug-like property as well. Our findings propose that natural compounds from garlic and onion can be used as potent inhibitors against the main protease of COVID-19, which could be helpful in combating the COVID-19 pandemic.

scholarly journals Molecular Docking and Dynamics Simulation Study of Hyrtios erectus Isolated Scalarane Sesterterpenes as Potential SARS-CoV-2 Dual Target Inhibitors

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 389
Author(s):  
Sameh S. Elhady ◽  
Reda F. A. Abdelhameed ◽  
Rania T. Malatani ◽  
Abdulrahman M. Alahdal ◽  
Hanin A. Bogari ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Md Simulation ◽  
Protein Complexes ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Main Protease ◽  
Simulation Parameters ◽  
Molecular Docking And Dynamics ◽  
Dual Target

Presently, the world is under the toll of pandemic coronavirus disease-2019 (COVID-19) outbreak caused by SARS-CoV-2. Lack of effective and safe therapeutics has stressed the scientific community for developing novel therapeutics capable of alleviating and stopping this pandemic. Within the presented study, molecular docking, ADME properties and all-atom molecular dynamic (MD) simulation, along with two standard antiviral agents (lopinavir and benzopurpurin-4B), were applied to investigate 15 scalaranes sesterterpenes natural compounds, purified from the Red Sea marine sponge Hyrtios erectus, as potential COVID-19 dual-target inhibitors. Following multi-step docking within COVID-19 main protease and Nsp15 endoribonuclease cavities, nine promising drug-like compounds exhibited higher docking scores as well as better interactions with the target’s crucial residues than those of reference ligands. Compounds 2, 6, 11, and 15, were predicted to simultaneously subdue the activity of the two COVID-19 targets. Dynamics behavior of the best-docked molecules, compounds 15 and 6, within COVID-19 target pockets showed substantial stability of ligand-protein complexes as presented via several MD simulation parameters. Furthermore, calculated free-binding energies from MD simulation illustrated significant ligand’s binding affinity towards respective target pockets. All provided findings supported the utility of scalarane-based sesterterpenes, particularly compounds 15 and 6, as promising lead candidates guiding the development of effective therapeutics against SARS-CoV-2.

scholarly journals A molecular docking study of SARS-CoV-2 main protease against phytochemicals of Siddha Medicinal herb Vilvam (Aegle marmelos)

2021 ◽  
Vol 12 (3) ◽  
pp. 506-512
Author(s):  
Nagappan A G ◽  
Krishnaveni M ◽  
Monika T ◽  
Thillaivanan S ◽  
Selvamoorthy G
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Study ◽  
Medicinal Herb ◽  
Aegle Marmelos ◽  
Ligand Complex ◽  
Main Protease ◽  
Study Results ◽  
The World ◽  
Novel Coronavirus

Background: In December of 2019, mysterious pneumonia was reported. A novel coronavirus (nCoV) was identified as the causative agent for this pneumonia; it is now known as coronavirus 2. This pandemic has caused widespread alarm around the world. Now, countries around the world are preparing for the third and fourth waves of COVID-19. Objective: This research aims to conduct In Silico computational studies of phytoconstituents in leaf extracts of the Siddha medicinal herb Aegle marmelos (Vilvam), which are commonly used in the treatment of viral fever and respiratory infectious diseases and may be effective against the current pandemic novel coronavirus disease. Methodology: In Silico molecular docking analysis was performed for all the active compounds present in the herb Aegle marmelos (Vilvam) with potential targets SARS-CoV-2 Main Protease (PDB ID: 7JQ5). The ligand structures were prepared and optimized by AutoDockTools. The active sites docking study was performed using Autodock Vina for all the compounds. The inhibitor compound MPI8 bound inSARS-CoV-2 main protease Protein-Ligand complex (PDB ID: 7JQ5) is considered as the reference inhibitor molecule of this study. Results: Molecular docking of the 14 bioactive phytochemicals compounds from Aegle marmelos leaves carried out towards the active site of SARS-CoV-2 Main Protease protein (PDB ID: 7JQ5). The interactions of these compounds were comparatively analyzed with the reference inhibitor MPI8 bound inSARS-CoV-2 Main Protease protein-ligand complex (PDB ID: 7JQ5). These phytochemicals exhibited effective molecular interactions with the active residues enumerating their differential inhibition potency. Conclusion: Further research and clinical trials are needed whether this herb can be implemented to effectively treat and manage COVID-19. 

scholarly journals Computational Studies Towards Identification of Lead Herbal Compounds of Medicinal Importance for Development of Nutraceutical Against COVID-19

2020 ◽  
Author(s):  
Amit Kumar Srivastav ◽  
Sanjeev Kumar Gupta ◽  
Umesh Kumar
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Md Simulation ◽  
Low Cost ◽  
Computational Studies ◽  
Ramachandran Plot ◽  
Lead Compounds ◽  
Cryo Electron Microscopy ◽  
Main Protease ◽  
In Silico Study

In the present study, we have performed the in-silico study of SARS-CoV-2 structure with different herbal compounds of medicinal importance. We selected four <a>viral key proteins of SARS-CoV-2 </a>structure i.e ACE-2 Receptor, Main Protease (Mpro), APO Form, Cryo- electron microscopy structure for the Molecular docking followed by the molecular dynamic simulation. Using this simple in silico approach based on the molecular docking and <a>MD simulation </a>of protein and phytochemicals, we have identified potential lead candidates for the development of low cost nutraceuticals, which can be used against SARS-CoV-2 virus. Our analysis suggested that phytochemicals obtained from <i>Phyllanthus emblica</i> and <i>Azadirachta indica</i> have the highest potential to bind with ACE2 receptor or main protease of SARS-CoV-2, inhibiting the protease enzymatic activity. The lead compounds of herbal origin were docked and simulated on viral key proteins of SARS-CoV-2 structure to evaluate the binding affinity of these phytochemicals along with the type of interaction and its stability in terms of <a>RMSD</a> and <a>Ramachandran plot</a>. Further, these results were also verified by drug likeness properties by using SwissADME software. Overall, our results suggest that out of 14 herbal compounds, Nimbolide and Withaferin-A has great potential to be developed as low-cost nutraceuticals against SARS-CoV-2 virus, which is the need of hour.

scholarly journals New Identified Anthocyanins from Sudanese Roselle:  Potential Candidates for inhibition of Xanthine Oxidase

2021 ◽  
Author(s):  
Arwa El-Naeem ◽  
Sahar Abdalla ◽  
Ibrahim Ahmed
Keyword(s):  
Molecular Docking ◽  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Binding Energies ◽  
Sensitive Technique ◽  
In Silico Docking ◽  
Docking Approach ◽  
Good Potential ◽  
Anthocyanin Pigments

Abstract This study aims to identify anthocyanin pigments in Sudanese roselle and examine their inhibitory activity toward xanthine oxidase (XO) enzyme via in silico docking approach. A number of four samples of Sudanese roselle (red and white) from different regions of Sudan were investigated by high sensitive technique, i.e. LC-MS to identify anthocyanins. Four anthocyanins were identified in all samples; delphinidin-3-glucoside (Dp-3-glu), cyanidin-3-sambubioside (Cy-3-sam), pelargonidin chloride (Pg Chloride), and petuinidin-3-glucoside (Pt-3-glu); in addition to one flavanol; gossypetin (Goss). The anthocyanins of the white samples are suggested to be presented in the yellowish or colorless pseudo base structures. The identified anthocyanins were tested against the inhibition toward xanthine oxidase via molecular docking. All anthocyanins were found to be excellent XO inhibitors superior to the most recent commercially used hyperuricemia drug; i.e. topiroxostat. The binding energies of the complexes (ligand-XO) are lower than the energy of the topiroxostat-XO complex. The binding energies order is: pt-3- dp-3-glu > cy-3-sam > goss > pg chloride. According to our investigation, roselle anthocyanins are considered as good potential future XO-inhibitors drugs; and promising candidates to treat several related diseases.

scholarly journals Virtual Screening of Phytochemicals Targeting the Main Protease and Spike Protein of SARS-CoV-2: An In silico Approach

2021 ◽  
Vol 2 (11) ◽  
pp. 1121-1131
Author(s):  
Pallavi Gulati ◽  
Aarti Yadav ◽  
Jatin Chadha ◽  
Sandeepa Singh
Keyword(s):  
In Silico ◽  
Drug Repurposing ◽  
Binding Pocket ◽  
Binding Energies ◽  
Ligand Complex ◽  
S Protein ◽  
High Binding ◽  
Main Protease ◽  
Pharmacologically Active

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an emerging virus responsible for the ongoing Coronavirus Disease 19 (COVID-19) pandemic. Despite the advent of COVID-19 vaccines, pandemic fatigue is still escalating as new SARS-CoV-2 variants emerge and vaccine shortages hit globally. Hence, drug repurposing remains an alternative strategy to combat SARS-CoV-2. For centuries, plants have served as natural reservoirs of pharmacologically active compounds with minimal cytotoxicity and promising antimicrobial and antiviral activities. In this light, the present study was undertaken to virtually screen 33 phytochemicals across various cultivars against the main protease (Mpro) and Spike (S) protein of SARS-CoV-2 using ADME analysis. 31 phytochemicals obeying Lipinski’s rules were subjected to molecular docking using AutoDock Vina. Docking scores were determined by selecting the best conformation of the protein-ligand complex that exhibited the highest affinity. The study identified withanone, licoflavone A, and silibinin to interact with the S protein at the hACE2-binding site with high binding energies. Similarly, myricitrin, withanone, naringenin, licoflavone A, and silibinin exhibited high binding affinities with the substrate-binding pocket of Mpro between the domains I and II. Interestingly, licoflavone A, silibinin, and withanone interacted with both Mpro and S proteins in silico. Further, drug-likeness studies indicated withanone to be the most readily bioavailable phytochemicals among the three shortlisted ligands. Therefore, phytochemicals can be regarded as potential leads for developing inhibitors against this mysterious virus. In vitro investigations are further warranted to prove their antiviral efficacy.

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