Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα
In this study, we utilized human DNA topoisomerase IIα as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore model that supplements the stat...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/24/13474 |
| _version_ | 1797503833438420992 |
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| author | Matej Janežič Katja Valjavec Kaja Bergant Loboda Barbara Herlah Iza Ogris Mirijam Kozorog Marjetka Podobnik Simona Golič Grdadolnik Gerhard Wolber Andrej Perdih |
| author_facet | Matej Janežič Katja Valjavec Kaja Bergant Loboda Barbara Herlah Iza Ogris Mirijam Kozorog Marjetka Podobnik Simona Golič Grdadolnik Gerhard Wolber Andrej Perdih |
| author_sort | Matej Janežič |
| collection | DOAJ |
| description | In this study, we utilized human DNA topoisomerase IIα as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore model that supplements the static structure-based-pharmacophore information with a dynamic component. Subsequently, derived pharmacophore models were employed in a virtual screening campaign of a library of natural compounds. Experimental evaluation identified flavonoid compounds with promising topoisomerase IIα catalytic inhibition and binding studies confirmed interaction with the ATPase domain. We constructed a binding model through docking and extensively investigated it with molecular dynamics MD simulations, essential dynamics, and MM-GBSA free energy calculations, thus reconnecting the new results to the initial dynophore-based screening model. We not only demonstrate a new design strategy that incorporates a dynamic component of molecular recognition, but also highlight new derivates in the established flavonoid class of topoisomerase II inhibitors. |
| first_indexed | 2024-03-10T03:56:00Z |
| format | Article |
| id | doaj.art-d9e7b114d1e74972aed9ab20e7944e36 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:56:00Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d9e7b114d1e74972aed9ab20e7944e362023-11-23T08:46:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122241347410.3390/ijms222413474Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIαMatej Janežič0Katja Valjavec1Kaja Bergant Loboda2Barbara Herlah3Iza Ogris4Mirijam Kozorog5Marjetka Podobnik6Simona Golič Grdadolnik7Gerhard Wolber8Andrej Perdih9National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaInstitute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2-4, 14195 Berlin, GermanyNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, SloveniaIn this study, we utilized human DNA topoisomerase IIα as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore model that supplements the static structure-based-pharmacophore information with a dynamic component. Subsequently, derived pharmacophore models were employed in a virtual screening campaign of a library of natural compounds. Experimental evaluation identified flavonoid compounds with promising topoisomerase IIα catalytic inhibition and binding studies confirmed interaction with the ATPase domain. We constructed a binding model through docking and extensively investigated it with molecular dynamics MD simulations, essential dynamics, and MM-GBSA free energy calculations, thus reconnecting the new results to the initial dynophore-based screening model. We not only demonstrate a new design strategy that incorporates a dynamic component of molecular recognition, but also highlight new derivates in the established flavonoid class of topoisomerase II inhibitors.https://www.mdpi.com/1422-0067/22/24/13474human DNA topoisomerase IIαcatalytic inhibitorsdynophore modelsdrug designmolecular simulationscancer research |
| spellingShingle | Matej Janežič Katja Valjavec Kaja Bergant Loboda Barbara Herlah Iza Ogris Mirijam Kozorog Marjetka Podobnik Simona Golič Grdadolnik Gerhard Wolber Andrej Perdih Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα International Journal of Molecular Sciences human DNA topoisomerase IIα catalytic inhibitors dynophore models drug design molecular simulations cancer research |
| title | Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα |
| title_full | Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα |
| title_fullStr | Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα |
| title_full_unstemmed | Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα |
| title_short | Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα |
| title_sort | dynophore based approach in virtual screening a case of human dna topoisomerase iiα |
| topic | human DNA topoisomerase IIα catalytic inhibitors dynophore models drug design molecular simulations cancer research |
| url | https://www.mdpi.com/1422-0067/22/24/13474 |
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