In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents
CDK-1 and PARP-1 play crucial roles in breast cancer progression. Compounds acting as CDK-1 and/or PARP-1 inhibitors can induct cell death in breast cancer with a selective synthetic lethality mechanism. A mixed treatment by means of CDK-1 and PARP-1 inhibitors resulted in radical breast cancer cell...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/18/13769 |
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| author | Alessia Bono Gabriele La Monica Federica Alamia Francesco Mingoia Carla Gentile Daniele Peri Antonino Lauria Annamaria Martorana |
| author_facet | Alessia Bono Gabriele La Monica Federica Alamia Francesco Mingoia Carla Gentile Daniele Peri Antonino Lauria Annamaria Martorana |
| author_sort | Alessia Bono |
| collection | DOAJ |
| description | CDK-1 and PARP-1 play crucial roles in breast cancer progression. Compounds acting as CDK-1 and/or PARP-1 inhibitors can induct cell death in breast cancer with a selective synthetic lethality mechanism. A mixed treatment by means of CDK-1 and PARP-1 inhibitors resulted in radical breast cancer cell growth reduction. Inhibitors with a dual target mechanism of action could arrest cancer progression by simultaneously blocking the DNA repair mechanism and cell cycle, resulting in advantageous monotherapy. To this aim, in the present work, we identified compound <b>645656</b> with a significant affinity for both CDK-1 and PARP-1 by a mixed ligand- and structure-based virtual screening protocol. The Biotarget Predictor Tool was used at first in a Multitarget mode to filter the large National Cancer Institute (NCI) database. Then, hierarchical docking studies were performed to further screen the compounds and evaluate the ligands binding mode, whose putative dual-target mechanism of action was investigated through the correlation between the antiproliferative activity data and the target proteins’ (CDK-1 and PARP-1) expression pattern. Finally, a Molecular Dynamics Simulation confirmed the high stability of the most effective selected compound <b>645656</b> in complex with both PARP-1 and CDK-1. |
| first_indexed | 2024-03-10T22:41:28Z |
| format | Article |
| id | doaj.art-addcda9d687447fe82667185c1d42872 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T22:41:28Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-addcda9d687447fe82667185c1d428722023-11-19T11:02:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124181376910.3390/ijms241813769In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer AgentsAlessia Bono0Gabriele La Monica1Federica Alamia2Francesco Mingoia3Carla Gentile4Daniele Peri5Antonino Lauria6Annamaria Martorana7Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, ItalyDipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, ItalyDipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, ItalyIstituto per lo Studio dei Materiali Nanostrutturati (ISMN), Consiglio Nazionale delle Ricerche (CNR), 90146 Palermo, ItalyDipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, ItalyDipartimento di Ingegneria dell’Innovazione Industriale e Digitale, Università degli Studi di Palermo, Viale 10 delle Scienze Ed. 6, 90128 Palermo, ItalyDipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, ItalyDipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, ItalyCDK-1 and PARP-1 play crucial roles in breast cancer progression. Compounds acting as CDK-1 and/or PARP-1 inhibitors can induct cell death in breast cancer with a selective synthetic lethality mechanism. A mixed treatment by means of CDK-1 and PARP-1 inhibitors resulted in radical breast cancer cell growth reduction. Inhibitors with a dual target mechanism of action could arrest cancer progression by simultaneously blocking the DNA repair mechanism and cell cycle, resulting in advantageous monotherapy. To this aim, in the present work, we identified compound <b>645656</b> with a significant affinity for both CDK-1 and PARP-1 by a mixed ligand- and structure-based virtual screening protocol. The Biotarget Predictor Tool was used at first in a Multitarget mode to filter the large National Cancer Institute (NCI) database. Then, hierarchical docking studies were performed to further screen the compounds and evaluate the ligands binding mode, whose putative dual-target mechanism of action was investigated through the correlation between the antiproliferative activity data and the target proteins’ (CDK-1 and PARP-1) expression pattern. Finally, a Molecular Dynamics Simulation confirmed the high stability of the most effective selected compound <b>645656</b> in complex with both PARP-1 and CDK-1.https://www.mdpi.com/1422-0067/24/18/13769breast cancerCDK-1PARP-1<i>olaparib</i><i>dinaciclib</i>multitarget mechanism |
| spellingShingle | Alessia Bono Gabriele La Monica Federica Alamia Francesco Mingoia Carla Gentile Daniele Peri Antonino Lauria Annamaria Martorana In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents International Journal of Molecular Sciences breast cancer CDK-1 PARP-1 <i>olaparib</i> <i>dinaciclib</i> multitarget mechanism |
| title | In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents |
| title_full | In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents |
| title_fullStr | In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents |
| title_full_unstemmed | In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents |
| title_short | In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents |
| title_sort | in silico mixed ligand structure based design of new cdk 1 parp 1 dual inhibitors as anti breast cancer agents |
| topic | breast cancer CDK-1 PARP-1 <i>olaparib</i> <i>dinaciclib</i> multitarget mechanism |
| url | https://www.mdpi.com/1422-0067/24/18/13769 |
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