COVID-19 Protease Inhibitor using Azole N-Mannich Bases: A Molecular Docking Approach

Coronaviruses are the largest group of viruses belonging to the Nidovirales order, which includes Coronaviridae, Arteriviridae and Roniviridae families. In this work, a molecular modeling technique is adopted to find out the excellent moiety to inhibit the protease enzyme which is present in the coronavirus. Autodock 4.2 tool was used to find out the docking score of 32 ligands. The molinspiration server helps to find out the drug-likeness property and whether these ligands having a binding towards the protease enzyme. The synthetic N-Mannich bases of azole were docked with COVID-19 main protease in complex with an inhibitor N3 (PDB id: 6lu7). Among 32 ligand molecules, around 25 ligands showed an excellent binding score when compared to the standard drug favipiravir. The presence of dimethyl group in the pyrazole nucleus helps good interaction with protease enzyme. Among the Mannich bases, the secondary amine mannich base of piperazine considered as the best derivative to inhibit the protease enzyme.

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Microwave-Assisted Synthesis, Molecular Docking Studies and Biological Evaluation of Benzothiazole Containing Novel Indole Derivatives

Asian Journal of Chemistry ◽

10.14233/ajchem.2021.23404 ◽

2021 ◽

Vol 33 (11) ◽

pp. 2755-2761

Author(s):

Shaheen Sultana ◽

P. Pandian ◽

B. Rajkamal

Keyword(s):

Molecular Docking ◽

Reaction Mechanism ◽

Anticancer Activity ◽

Mannich Base ◽

Docking Studies ◽

Biological Evaluation ◽

Indole Derivatives ◽

Standard Drug ◽

Molecular Docking Studies ◽

Microwave Assisted

The synthesis of novel indole derivatives 4a-o using a microwave assisted method via Schiff’s base and Mannich base reaction mechanism was described. Compounds 3a-c were synthesized via reaction of 2-amino benzothiazole with substituted isatin by Schiff base reaction mechanism. Also, indole derivatives 4a-o were synthesized via reaction of compounds 3a-c with substituted benzaldehydes by Mannich base reaction. The biological potentials of the newly synthesized indole derivatives were evaluated for their anthelmintic activity and in vitro anticancer activity by MTT assay. The anticancer activity results suggested that indole derivatives 4c-o have activity against MCF-7 and SKOV3 cells in comparison with doxorubicin as standard drug. Furthermore, the molecular docking studies of these novel derivatives of indole showed good agreement with the biological results when their binding pattern and affinity towards the active site of EGFR was also investigated.

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Computational screening of dual inhibitors from FDA approved antiviral drugs on SARS-CoV-2 spike protein and the main protease using molecular docking approach

Acta Virologica ◽

10.4149/av_2021_208 ◽

2021 ◽

Vol 65 (02) ◽

pp. 160-172

Author(s):

Shanthi Sabarimurugan ◽

Indu Purushothaman ◽

Rajarajan Swaminathan ◽

Arun Dharmarajan ◽

Sudha Warrier ◽

...

Keyword(s):

Molecular Docking ◽

Antiviral Drugs ◽

Spike Protein ◽

Computational Screening ◽

Main Protease ◽

Docking Approach ◽

Dual Inhibitors

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Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

10.26434/chemrxiv.12118857.v1 ◽

2020 ◽

Author(s):

Mahmudul Hasan ◽

Md Sorwer Alam Parvez ◽

Kazi Faizul Azim ◽

Abdus Shukur Imran ◽

Topu Raihan ◽

...

Keyword(s):

Molecular Docking ◽

Drug Repurposing ◽

Pharmacokinetic Parameters ◽

The Novel ◽

Drug Candidates ◽

Target Drug ◽

Global Pandemic ◽

Main Protease ◽

Docking Approach ◽

Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

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Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

10.26434/chemrxiv.12179202 ◽

2020 ◽

Author(s):

pooja singh ◽

Angkita Sharma ◽

Shoma Paul Nandi

Keyword(s):

Molecular Docking ◽

Antiviral Drug ◽

Cyclopiazonic Acid ◽

Docking Study ◽

Molecular Docking Study ◽

Docking Score ◽

Protease Enzyme ◽

Main Protease

<p>Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease M<sup>pro</sup>, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in <i>Aspergillus flavus</i> and <i>Aspergillus oryzae</i> fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth <i>in- vitro</i> and <i>in-vivo</i>.<b> </b></p>

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MOLECULAR DOCKING STUDY TO IDENTIFY POTENTIAL INHIBITOR OF COVID-19 MAIN PROTEASE ENZYME: AN IN-SILICO APPROACH

10.26434/chemrxiv.12170904 ◽

2020 ◽

Author(s):

Anurag Agrawal ◽

Nem Kumar Jain ◽

Neeraj Kumar ◽

Giriraj T Kulkarni

Keyword(s):

Molecular Docking ◽

Active Site ◽

Docking Study ◽

Molecular Docking Study ◽

Potential Threat ◽

Discovery Studio ◽

Chemical Structures ◽

Potential Inhibitor ◽

Protease Enzyme ◽

Main Protease

This study belongs to identification of suitable COVID-19 inhibitors<br><div><br></div><div>Coronavirus became pandemic very soon and is a potential threat to human lives across the globe. No approved drug is currently available therefore an urgent need has been developed for any antiviral therapy for COVID-19. For the molecular docking study, ten herbal molecules have been included in the current study. The three-dimensional chemical structures of molecules were prepared through ChemSketch 2015 freeware. Molecular docking study was performed using AutoDock 4.2 simulator and Discovery studio 4.5 was employed to predict the active site of target enzyme. Result indicated that all-natural molecules found in the active site of enzyme after molecular docking. Oxyacanthine and Hypericin (-10.990 and -9.05 and kcal/mol respectively) have shown good binding efficacy among others but Oxyacanthine was the only natural product which made some of necessary interactions with residues in the enzyme require for target inhibition. Therefore Oxyacanthine may be considered to be potential inhibitor of main protease enzyme of virus but need to be explored for further drug development process. <br></div>

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Identification of Bioactive Phytoconstituents from the Plant Euphorbia hirta as Potential Inhibitor of SARS-CoV-2: an In-Silico Approach

Biointerface Research in Applied Chemistry ◽

10.33263/briac122.13851396 ◽

2021 ◽

Vol 12 (2) ◽

pp. 1385-1396

Keyword(s):

Molecular Docking ◽

In Silico ◽

Biological Activities ◽

Specific Treatment ◽

Docking Study ◽

Docking Studies ◽

Molecular Docking Study ◽

Standard Drug ◽

Euphorbia Hirta ◽

Main Protease

Currently, the entire globe is under the deadliest pandemic of Covid-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). At present, no specific treatment is available to combat COVID-19 infection. Euphorbia hirta (Euphorbiaceae) have been reported for a variety of biological activities, including antiviral. The present investigation aimed to identify potential phytoconstituents of the plant E. hirta from the category flavonoids and coumarins against the SARS-CoV-2 using in silico approach. The molecular docking studies were performed using two different targets of SARS-CoV-2, namely Main protease (Mpro; PDB ID: 6M2N) and RNA-dependent RNA polymerase (RdRp; PDB ID: 7BW4). Based on the molecular docking study in comparison with standard drug, four compounds, namely Euphrobianin, Quercetin, 3-o-alpha-rhamnoside, Isoquercitrin, and rutin, were screened against the target Mpro. Three phytoconstituents, euphorbianin, myricetin, and rutin, were screened against the target RdRp. In the in silico toxicity studies of screened phytoconstituents, except myrectin all were predicted safe. Results of euphorbianin and rutin were found more interesting as both compounds had high binding affinity against both targets. Finally, we want to conclude that euphrobianin, quercetin 3-o-alpha-rhamnoside, isoquercitrin, and rutin could be further explored rapidly as they may have the potential to fight against COVID-19.

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Molecular Docking Reveals the Potential of Aliskiren, Dipyridamole, Mopidamol, Rosuvastatin, Rolitetracycline and Metamizole to Inhibit COVID-19 Virus Main Protease

10.26434/chemrxiv.12061302 ◽

2020 ◽

Author(s):

Omar Aly

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Drug Repurposing ◽

Binding Mode ◽

Type I ◽

Catalytic Center ◽

Protease Enzyme ◽

Main Protease ◽

Renin Inhibition ◽

Better Than

<p>Drug repurposing is a fast way to rapidly discover a drug for clinical use. In such circumstances of the spreading of the highly contagious COVID-19, searching for already known drugs is a worldwide demand. In this study, many drugs were evaluated by molecular docking. Among the test compounds, aliskiren (the best), dipyridamole, mopidamol and rosuvastatin showed higher energies of binding than that of the co-crystallized ligand N3 with COVID-19 main protease M<sup>pro</sup>. Rolitetracycline showed the best binding with the catalytic center of the protease enzyme through binding with CYS 145 and HIS 41. Metamizole showed about 86 % of the binding energy of the ligand N3 while the protease inhibitor darunavir showed little bit lower binding energy than N3. These results are promising for using these drugs in the treatment and management of the spreading of COVID-19 virus. Also, it could stimulate clinical trials for the use of these drugs by systemic or <b>inhalation</b> route.</p><p></p><p>The results stimulate the evaluation of these drugs as anti COVID-19 especially aliskiren which showed the highest score of binding with the binding site of N3. This will be added to its renin inhibition and advantage of renin inhibition and possibility of the reduced expression of ACE2[12]. Dipyridamole and mopidamol showed a potential to be more M<sup>pro </sup>inhibitor than ligand N3 and darunavir. Also, dipyridamole has the property of antiviral activity beside its use to decrease the hypercoagulabilty that happens due to COVID infection in addition to the property of promoting type I interferon (IFN) responses and protect mice from viral pneumonia [30]. Rolitetracycling is an amazing in its binding mode in the active site of the protease pocket it seemed as it is tailored to be buried in that pocket. Mopidamol and rosuvastatin are slightly better than the co-crystallized ligand N3 and darunavir in binding mode which nominate the as COVID-19 protease inhibitors. Hopefully this study will help in the repurposing a drug for the treatment of COVID-19.</p><p></p>

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

Biointerface Research in Applied Chemistry ◽

10.33263/briac111.79817993 ◽

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.

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