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Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment
Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1–7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enter...
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Published in: | Journal of molecular graphics & modelling 2020-11, Vol.100, p.107697-107697, Article 107697 |
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description | Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1–7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor’s active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor’s critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.
[Display omitted]
•A drug library of 7173 ligands was screened against ACE2 using molecular docking.•The predicted ACE2–ligand complexes were optimized via molecular mechanics.•On closer examination, eight promising repositionable drug candidates were proposed.•The drugs, unmodified as they are, may serve as entry inhibitors of SARS-CoV-2.•Their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors. |
doi_str_mv | 10.1016/j.jmgm.2020.107697 |
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[Display omitted]
•A drug library of 7173 ligands was screened against ACE2 using molecular docking.•The predicted ACE2–ligand complexes were optimized via molecular mechanics.•On closer examination, eight promising repositionable drug candidates were proposed.•The drugs, unmodified as they are, may serve as entry inhibitors of SARS-CoV-2.•Their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors.</description><identifier>ISSN: 1093-3263</identifier><identifier>EISSN: 1873-4243</identifier><identifier>DOI: 10.1016/j.jmgm.2020.107697</identifier><identifier>PMID: 32739642</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ACE2 ; Amino Acid Motifs ; Angiotensin-Converting Enzyme 2 ; Angiotensin-Converting Enzyme Inhibitors - chemistry ; Antiviral Agents - chemistry ; Betacoronavirus - chemistry ; Betacoronavirus - enzymology ; Carbazoles - chemistry ; Catalytic Domain ; Coronavirus Infections - drug therapy ; Coronavirus Infections - virology ; COVID-19 ; Drug Repositioning ; Dyphylline - analogs & derivatives ; Dyphylline - chemistry ; Entry inhibitor ; Host-Pathogen Interactions ; Humans ; Hydroxamic Acids - chemistry ; Ligands ; Molecular Docking Simulation ; Pandemics ; Paromomycin - analogs & derivatives ; Paromomycin - chemistry ; Pemetrexed - chemistry ; Peptidyl-Dipeptidase A - chemistry ; Peptidyl-Dipeptidase A - metabolism ; Pneumonia, Viral - drug therapy ; Pneumonia, Viral - virology ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Structure, Secondary ; SARS-CoV-2 ; Small Molecule Libraries - chemistry ; Structure-Activity Relationship ; Thermodynamics</subject><ispartof>Journal of molecular graphics & modelling, 2020-11, Vol.100, p.107697-107697, Article 107697</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><rights>2020 Elsevier Inc. All rights reserved. 2020 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-bc7f0b482f5cffa861a34aad6d4e21089dae158472f98c0bf7ee0682a7149cbb3</citedby><cites>FETCH-LOGICAL-c455t-bc7f0b482f5cffa861a34aad6d4e21089dae158472f98c0bf7ee0682a7149cbb3</cites><orcidid>0000-0002-9964-6383</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32739642$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Teralı, Kerem</creatorcontrib><creatorcontrib>Baddal, Buket</creatorcontrib><creatorcontrib>Gülcan, Hayrettin Ozan</creatorcontrib><title>Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment</title><title>Journal of molecular graphics & modelling</title><addtitle>J Mol Graph Model</addtitle><description>Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1–7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor’s active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor’s critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.
[Display omitted]
•A drug library of 7173 ligands was screened against ACE2 using molecular docking.•The predicted ACE2–ligand complexes were optimized via molecular mechanics.•On closer examination, eight promising repositionable drug candidates were proposed.•The drugs, unmodified as they are, may serve as entry inhibitors of SARS-CoV-2.•Their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors.</description><subject>ACE2</subject><subject>Amino Acid Motifs</subject><subject>Angiotensin-Converting Enzyme 2</subject><subject>Angiotensin-Converting Enzyme Inhibitors - chemistry</subject><subject>Antiviral Agents - chemistry</subject><subject>Betacoronavirus - chemistry</subject><subject>Betacoronavirus - enzymology</subject><subject>Carbazoles - chemistry</subject><subject>Catalytic Domain</subject><subject>Coronavirus Infections - drug therapy</subject><subject>Coronavirus Infections - virology</subject><subject>COVID-19</subject><subject>Drug Repositioning</subject><subject>Dyphylline - analogs & derivatives</subject><subject>Dyphylline - chemistry</subject><subject>Entry inhibitor</subject><subject>Host-Pathogen Interactions</subject><subject>Humans</subject><subject>Hydroxamic Acids - chemistry</subject><subject>Ligands</subject><subject>Molecular Docking Simulation</subject><subject>Pandemics</subject><subject>Paromomycin - analogs & derivatives</subject><subject>Paromomycin - chemistry</subject><subject>Pemetrexed - chemistry</subject><subject>Peptidyl-Dipeptidase A - chemistry</subject><subject>Peptidyl-Dipeptidase A - metabolism</subject><subject>Pneumonia, Viral - drug therapy</subject><subject>Pneumonia, Viral - virology</subject><subject>Protein Binding</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Protein Structure, Secondary</subject><subject>SARS-CoV-2</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Structure-Activity Relationship</subject><subject>Thermodynamics</subject><issn>1093-3263</issn><issn>1873-4243</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9Ud2K1DAULqK46-oLeCF5gY75m6YVEZZx1YGF9UK9DWl6Mj1Dm5YkHVYfxac1ZXTRG6_OT873E76ieMnohlFWvT5ujuNh3HDK14WqGvWouGS1EqXkUjzOPW1EKXglLopnMR4ppaKm6mlxIbgSTSX5ZfHzc8ApYMIf6A9knhL4hGYg17sbTtD32GKaQswtST2Q3d23_fuSNWQ2voMR7Ruy9xEPfYrEhWkkhozTAHYZTCAj2N54tLE0MWJM0JGYwmLTEqBsTczzCUNasly0AcCvFuB-hoBjtvG8eOLMEOHF73pVfP1w82X3qby9-7jfXd-WVm63qWytcrSVNXdb65ypK2aENKarOgmc0brpDLBtLRV3TW1p6xQArWpuFJONbVtxVbw7885LO0Jns3Qwg56zCxO-68mg_vfFY68P00kroVRNWSbgZwIbphgDuAcso3pNSh_1mpRek9LnpDLo1d-qD5A_0eSDt-cDyH8_IQQdLYK30GEAm3Q34f_4fwHBuapU</recordid><startdate>20201101</startdate><enddate>20201101</enddate><creator>Teralı, Kerem</creator><creator>Baddal, Buket</creator><creator>Gülcan, Hayrettin Ozan</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9964-6383</orcidid></search><sort><creationdate>20201101</creationdate><title>Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment</title><author>Teralı, Kerem ; Baddal, Buket ; Gülcan, Hayrettin Ozan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-bc7f0b482f5cffa861a34aad6d4e21089dae158472f98c0bf7ee0682a7149cbb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>ACE2</topic><topic>Amino Acid Motifs</topic><topic>Angiotensin-Converting Enzyme 2</topic><topic>Angiotensin-Converting Enzyme Inhibitors - chemistry</topic><topic>Antiviral Agents - chemistry</topic><topic>Betacoronavirus - chemistry</topic><topic>Betacoronavirus - enzymology</topic><topic>Carbazoles - chemistry</topic><topic>Catalytic Domain</topic><topic>Coronavirus Infections - drug therapy</topic><topic>Coronavirus Infections - virology</topic><topic>COVID-19</topic><topic>Drug Repositioning</topic><topic>Dyphylline - analogs & derivatives</topic><topic>Dyphylline - chemistry</topic><topic>Entry inhibitor</topic><topic>Host-Pathogen Interactions</topic><topic>Humans</topic><topic>Hydroxamic Acids - chemistry</topic><topic>Ligands</topic><topic>Molecular Docking Simulation</topic><topic>Pandemics</topic><topic>Paromomycin - analogs & derivatives</topic><topic>Paromomycin - chemistry</topic><topic>Pemetrexed - chemistry</topic><topic>Peptidyl-Dipeptidase A - chemistry</topic><topic>Peptidyl-Dipeptidase A - metabolism</topic><topic>Pneumonia, Viral - drug therapy</topic><topic>Pneumonia, Viral - virology</topic><topic>Protein Binding</topic><topic>Protein Interaction Domains and Motifs</topic><topic>Protein Structure, Secondary</topic><topic>SARS-CoV-2</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Structure-Activity Relationship</topic><topic>Thermodynamics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Teralı, Kerem</creatorcontrib><creatorcontrib>Baddal, Buket</creatorcontrib><creatorcontrib>Gülcan, Hayrettin Ozan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of molecular graphics & modelling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Teralı, Kerem</au><au>Baddal, Buket</au><au>Gülcan, Hayrettin Ozan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment</atitle><jtitle>Journal of molecular graphics & modelling</jtitle><addtitle>J Mol Graph Model</addtitle><date>2020-11-01</date><risdate>2020</risdate><volume>100</volume><spage>107697</spage><epage>107697</epage><pages>107697-107697</pages><artnum>107697</artnum><issn>1093-3263</issn><eissn>1873-4243</eissn><abstract>Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1–7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor’s active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor’s critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.
[Display omitted]
•A drug library of 7173 ligands was screened against ACE2 using molecular docking.•The predicted ACE2–ligand complexes were optimized via molecular mechanics.•On closer examination, eight promising repositionable drug candidates were proposed.•The drugs, unmodified as they are, may serve as entry inhibitors of SARS-CoV-2.•Their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32739642</pmid><doi>10.1016/j.jmgm.2020.107697</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-9964-6383</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | ACE2 Amino Acid Motifs Angiotensin-Converting Enzyme 2 Angiotensin-Converting Enzyme Inhibitors - chemistry Antiviral Agents - chemistry Betacoronavirus - chemistry Betacoronavirus - enzymology Carbazoles - chemistry Catalytic Domain Coronavirus Infections - drug therapy Coronavirus Infections - virology COVID-19 Drug Repositioning Dyphylline - analogs & derivatives Dyphylline - chemistry Entry inhibitor Host-Pathogen Interactions Humans Hydroxamic Acids - chemistry Ligands Molecular Docking Simulation Pandemics Paromomycin - analogs & derivatives Paromomycin - chemistry Pemetrexed - chemistry Peptidyl-Dipeptidase A - chemistry Peptidyl-Dipeptidase A - metabolism Pneumonia, Viral - drug therapy Pneumonia, Viral - virology Protein Binding Protein Interaction Domains and Motifs Protein Structure, Secondary SARS-CoV-2 Small Molecule Libraries - chemistry Structure-Activity Relationship Thermodynamics |
title | Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: Insights from a molecular mechanics-assisted structure-based virtual screening experiment |
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