In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes
New models for ACE2 receptor binding, based on QSAR and docking algorithms were developed, using XRD structural data and ChEMBL 26 database hits as training sets. The selectivity of the potential ACE2-binding ligands towards Neprilysin (NEP) and ACE was evaluated. The Enamine screening collection (3...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/17/5400 |
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| author | Alexey V. Rayevsky Andrii S. Poturai Iryna O. Kravets Alexander E. Pashenko Tatiana A. Borisova Ganna M. Tolstanova Dmitriy M. Volochnyuk Petro O. Borysko Olga B. Vadzyuk Diana O. Alieksieieva Yuliana Zabolotna Olga Klimchuk Dragos Horvath Gilles Marcou Sergey V. Ryabukhin Alexandre Varnek |
| author_facet | Alexey V. Rayevsky Andrii S. Poturai Iryna O. Kravets Alexander E. Pashenko Tatiana A. Borisova Ganna M. Tolstanova Dmitriy M. Volochnyuk Petro O. Borysko Olga B. Vadzyuk Diana O. Alieksieieva Yuliana Zabolotna Olga Klimchuk Dragos Horvath Gilles Marcou Sergey V. Ryabukhin Alexandre Varnek |
| author_sort | Alexey V. Rayevsky |
| collection | DOAJ |
| description | New models for ACE2 receptor binding, based on QSAR and docking algorithms were developed, using XRD structural data and ChEMBL 26 database hits as training sets. The selectivity of the potential ACE2-binding ligands towards Neprilysin (NEP) and ACE was evaluated. The Enamine screening collection (3.2 million compounds) was virtually screened according to the above models, in order to find possible ACE2-chemical probes, useful for the study of SARS-CoV2-induced neurological disorders. An enzymology inhibition assay for ACE2 was optimized, and the combined diversified set of predicted selective ACE2-binding molecules from QSAR modeling, docking, and ultrafast docking was screened in vitro. The in vitro hits included two novel chemotypes suitable for further optimization. |
| first_indexed | 2024-03-10T01:31:19Z |
| format | Article |
| id | doaj.art-178e51ad7468417082ac12b519f61623 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T01:31:19Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-178e51ad7468417082ac12b519f616232023-11-23T13:41:19ZengMDPI AGMolecules1420-30492022-08-012717540010.3390/molecules27175400In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical ProbesAlexey V. Rayevsky0Andrii S. Poturai1Iryna O. Kravets2Alexander E. Pashenko3Tatiana A. Borisova4Ganna M. Tolstanova5Dmitriy M. Volochnyuk6Petro O. Borysko7Olga B. Vadzyuk8Diana O. Alieksieieva9Yuliana Zabolotna10Olga Klimchuk11Dragos Horvath12Gilles Marcou13Sergey V. Ryabukhin14Alexandre Varnek15Enamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkraineEnamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkraineEnamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkraineEnamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkrainePalladin Institute of Biochemistry of the National Academy of Sciences of Ukraine, 9 Leontovitcha Street, 01054 Kyiv, UkraineEducational and Scientific Institute of High Technologies, Taras Shevchenko National University of Kyiv, 60 Volodymyrska Street, 01033 Kyiv, UkraineEnamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkraineEnamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkraineEnamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkraineEnamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkraineLaboratory of Chemoinformatics, University of Strasbourg, 4, rue B. Pascal, 67081 Strasbourg, FranceLaboratory of Chemoinformatics, University of Strasbourg, 4, rue B. Pascal, 67081 Strasbourg, FranceLaboratory of Chemoinformatics, University of Strasbourg, 4, rue B. Pascal, 67081 Strasbourg, FranceLaboratory of Chemoinformatics, University of Strasbourg, 4, rue B. Pascal, 67081 Strasbourg, FranceEnamine Ltd., 78 Chervonotkatska Street, 02660 Kyiv, UkraineLaboratory of Chemoinformatics, University of Strasbourg, 4, rue B. Pascal, 67081 Strasbourg, FranceNew models for ACE2 receptor binding, based on QSAR and docking algorithms were developed, using XRD structural data and ChEMBL 26 database hits as training sets. The selectivity of the potential ACE2-binding ligands towards Neprilysin (NEP) and ACE was evaluated. The Enamine screening collection (3.2 million compounds) was virtually screened according to the above models, in order to find possible ACE2-chemical probes, useful for the study of SARS-CoV2-induced neurological disorders. An enzymology inhibition assay for ACE2 was optimized, and the combined diversified set of predicted selective ACE2-binding molecules from QSAR modeling, docking, and ultrafast docking was screened in vitro. The in vitro hits included two novel chemotypes suitable for further optimization.https://www.mdpi.com/1420-3049/27/17/5400QSAR modelingmolecular dockingNeprilysinangiotensin-converting enzymeselective ACE2 enzyme bindingblood-brain barrier penetration |
| spellingShingle | Alexey V. Rayevsky Andrii S. Poturai Iryna O. Kravets Alexander E. Pashenko Tatiana A. Borisova Ganna M. Tolstanova Dmitriy M. Volochnyuk Petro O. Borysko Olga B. Vadzyuk Diana O. Alieksieieva Yuliana Zabolotna Olga Klimchuk Dragos Horvath Gilles Marcou Sergey V. Ryabukhin Alexandre Varnek In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes Molecules QSAR modeling molecular docking Neprilysin angiotensin-converting enzyme selective ACE2 enzyme binding blood-brain barrier penetration |
| title | In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes |
| title_full | In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes |
| title_fullStr | In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes |
| title_full_unstemmed | In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes |
| title_short | In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes |
| title_sort | in vitro evaluation of in silico screening approaches in search for selective ace2 binding chemical probes |
| topic | QSAR modeling molecular docking Neprilysin angiotensin-converting enzyme selective ACE2 enzyme binding blood-brain barrier penetration |
| url | https://www.mdpi.com/1420-3049/27/17/5400 |
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