<i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 s...

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Autores principales:	Mohamed S. Alesawy, Eslam B. Elkaeed, Aisha A. Alsfouk, Ahmed M. Metwaly, Ibrahim H. Eissa
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	COVID-19 papain-like protease pharmacophore molecular docking ADMET toxicity Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/513bf3d528024dc085c0168f3589cda3
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spelling	oai:doaj.org-article:513bf3d528024dc085c0168f3589cda32021-11-11T18:34:17Z<i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies10.3390/molecules262165931420-3049https://doaj.org/article/513bf3d528024dc085c0168f3589cda32021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6593https://doaj.org/toc/1420-3049Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives <b>34</b> and <b>58</b> were better than the co-crystallized ligand while derivatives <b>17</b>, <b>28</b>, <b>31</b>, <b>40</b>, <b>41</b>, <b>43</b>, <b>47</b>, <b>54</b>, and <b>65</b> exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives <b>28</b>, <b>34</b>, and <b>47</b> have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of <b>28</b>, <b>34</b>, and <b>47</b> against the co-crystallized ligand in a DFT study indicated that <b>28</b> is the most promising candidate to interact with the target receptor (PLpro).Mohamed S. AlesawyEslam B. ElkaeedAisha A. AlsfoukAhmed M. MetwalyIbrahim H. EissaMDPI AGarticleCOVID-19papain-like proteasepharmacophoremolecular dockingADMETtoxicityOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6593, p 6593 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 papain-like protease pharmacophore molecular docking ADMET toxicity Organic chemistry QD241-441
spellingShingle	COVID-19 papain-like protease pharmacophore molecular docking ADMET toxicity Organic chemistry QD241-441 Mohamed S. Alesawy Eslam B. Elkaeed Aisha A. Alsfouk Ahmed M. Metwaly Ibrahim H. Eissa <i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies
description	Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives <b>34</b> and <b>58</b> were better than the co-crystallized ligand while derivatives <b>17</b>, <b>28</b>, <b>31</b>, <b>40</b>, <b>41</b>, <b>43</b>, <b>47</b>, <b>54</b>, and <b>65</b> exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives <b>28</b>, <b>34</b>, and <b>47</b> have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of <b>28</b>, <b>34</b>, and <b>47</b> against the co-crystallized ligand in a DFT study indicated that <b>28</b> is the most promising candidate to interact with the target receptor (PLpro).
format	article
author	Mohamed S. Alesawy Eslam B. Elkaeed Aisha A. Alsfouk Ahmed M. Metwaly Ibrahim H. Eissa
author_facet	Mohamed S. Alesawy Eslam B. Elkaeed Aisha A. Alsfouk Ahmed M. Metwaly Ibrahim H. Eissa
author_sort	Mohamed S. Alesawy
title	<i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies
title_short	<i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies
title_full	<i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies
title_fullStr	<i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies
title_full_unstemmed	<i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies
title_sort	<i>in silico</i> screening of semi-synthesized compounds as potential inhibitors for sars-cov-2 papain-like protease: pharmacophoric features, molecular docking, admet, toxicity and dft studies
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/513bf3d528024dc085c0168f3589cda3
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<i>In Silico</i> Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies

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