Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations
Hsp90 C-terminal domain (CTD) inhibitors are promising novel agents for cancer treatment, as they do not induce the heat shock response associated with Hsp90 N-terminal inhibitors. One challenge associated with CTD inhibitors is the lack of a co-crystallized complex, requiring the use of predicted a...
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MDPI AG
2020-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/18/6898 |
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| author | Tihomir Tomašič Martina Durcik Bradley M. Keegan Darja Gramec Skledar Živa Zajec Brian S. J. Blagg Sharon D. Bryant |
| author_facet | Tihomir Tomašič Martina Durcik Bradley M. Keegan Darja Gramec Skledar Živa Zajec Brian S. J. Blagg Sharon D. Bryant |
| author_sort | Tihomir Tomašič |
| collection | DOAJ |
| description | Hsp90 C-terminal domain (CTD) inhibitors are promising novel agents for cancer treatment, as they do not induce the heat shock response associated with Hsp90 N-terminal inhibitors. One challenge associated with CTD inhibitors is the lack of a co-crystallized complex, requiring the use of predicted allosteric apo pocket, limiting structure-based (SB) design approaches. To address this, a unique approach that enables the derivation and analysis of interactions between ligands and proteins from molecular dynamics (MD) trajectories was used to derive pharmacophore models for virtual screening (VS) and identify suitable binding sites for SB design. Furthermore, ligand-based (LB) pharmacophores were developed using a set of CTD inhibitors to compare VS performance with the MD derived models. Virtual hits identified by VS with both SB and LB models were tested for antiproliferative activity. Compounds <b>9</b> and <b>11</b> displayed antiproliferative activities in MCF-7 and Hep G2 cancer cell lines. Compound <b>11</b> inhibited Hsp90-dependent refolding of denatured luciferase and induced the degradation of Hsp90 clients without the concomitant induction of Hsp70 levels. Furthermore, compound <b>11</b> offers a unique scaffold that is promising for the further synthetic optimization and development of molecules needed for the evaluation of the Hsp90 CTD as a target for the development of anticancer drugs. |
| first_indexed | 2024-03-10T16:11:59Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:11:59Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cba7f550859549e28530b0a56975bae52023-11-20T14:25:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-09-012118689810.3390/ijms21186898Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics SimulationsTihomir Tomašič0Martina Durcik1Bradley M. Keegan2Darja Gramec Skledar3Živa Zajec4Brian S. J. Blagg5Sharon D. Bryant6Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, SloveniaDepartment of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USAFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, SloveniaDepartment of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USAInte:Ligand Softwareentwicklungs- und Consulting GmbH, Mariahilferstrasse 74B, 1070 Vienna, AustriaHsp90 C-terminal domain (CTD) inhibitors are promising novel agents for cancer treatment, as they do not induce the heat shock response associated with Hsp90 N-terminal inhibitors. One challenge associated with CTD inhibitors is the lack of a co-crystallized complex, requiring the use of predicted allosteric apo pocket, limiting structure-based (SB) design approaches. To address this, a unique approach that enables the derivation and analysis of interactions between ligands and proteins from molecular dynamics (MD) trajectories was used to derive pharmacophore models for virtual screening (VS) and identify suitable binding sites for SB design. Furthermore, ligand-based (LB) pharmacophores were developed using a set of CTD inhibitors to compare VS performance with the MD derived models. Virtual hits identified by VS with both SB and LB models were tested for antiproliferative activity. Compounds <b>9</b> and <b>11</b> displayed antiproliferative activities in MCF-7 and Hep G2 cancer cell lines. Compound <b>11</b> inhibited Hsp90-dependent refolding of denatured luciferase and induced the degradation of Hsp90 clients without the concomitant induction of Hsp70 levels. Furthermore, compound <b>11</b> offers a unique scaffold that is promising for the further synthetic optimization and development of molecules needed for the evaluation of the Hsp90 CTD as a target for the development of anticancer drugs.https://www.mdpi.com/1422-0067/21/18/6898allostericcancerHsp90inhibitormolecular dynamicspharmacophores |
| spellingShingle | Tihomir Tomašič Martina Durcik Bradley M. Keegan Darja Gramec Skledar Živa Zajec Brian S. J. Blagg Sharon D. Bryant Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations International Journal of Molecular Sciences allosteric cancer Hsp90 inhibitor molecular dynamics pharmacophores |
| title | Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations |
| title_full | Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations |
| title_fullStr | Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations |
| title_full_unstemmed | Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations |
| title_short | Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations |
| title_sort | discovery of novel hsp90 c terminal inhibitors using 3d pharmacophores derived from molecular dynamics simulations |
| topic | allosteric cancer Hsp90 inhibitor molecular dynamics pharmacophores |
| url | https://www.mdpi.com/1422-0067/21/18/6898 |
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