Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer
The protein kinase Mps1 (monopolar spindle 1) is an important regulator of the Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system of higher organisms that monitors the proper bipolar attachment of all chromosomes to the mitotic spindle during cell division. Defects in th...
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/14228 |
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| author | Lauren Pugh Alisha Pancholi Priscila Celeste Purat Sandra Agudo-Alvarez Raúl Benito-Arenas Agatha Bastida Victor M. Bolanos-Garcia |
| author_facet | Lauren Pugh Alisha Pancholi Priscila Celeste Purat Sandra Agudo-Alvarez Raúl Benito-Arenas Agatha Bastida Victor M. Bolanos-Garcia |
| author_sort | Lauren Pugh |
| collection | DOAJ |
| description | The protein kinase Mps1 (monopolar spindle 1) is an important regulator of the Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system of higher organisms that monitors the proper bipolar attachment of all chromosomes to the mitotic spindle during cell division. Defects in the catalytic activity and the transcription regulation of Mps1 are associated with genome instability, aneuploidy, and cancer. Moreover, multiple Mps1 missense and frameshift mutations have been reported in a wide range of types of cancer of different tissue origin. Due to these features, Mps1 arises as one promising drug target for cancer therapy. In this contribution, we developed a computational biology approach to study the dynamics of human Mps1 kinase interaction with isoflavones, a class of natural flavonoids, and compared their predicted mode of binding with that observed in the crystal structure of Mps1 in complex with reversine, a small-sized inhibitor of Mps1 and Aurora B kinases. We concluded that isoflavones define a chemical scaffold that can be used to develop new Mps1 inhibitors for the treatment of cancer associated with Mps1 amplification and aberrant chromosome segregation. In a broader context, the present report illustrates how modern chemoinformatics approaches can accelerate drug development in oncology. |
| first_indexed | 2024-03-09T18:16:55Z |
| format | Article |
| id | doaj.art-aee9fb3a3d534e8bad7cc63009f20af5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:16:55Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-aee9fb3a3d534e8bad7cc63009f20af52023-11-24T08:40:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221422810.3390/ijms232214228Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of CancerLauren Pugh0Alisha Pancholi1Priscila Celeste Purat2Sandra Agudo-Alvarez3Raúl Benito-Arenas4Agatha Bastida5Victor M. Bolanos-Garcia6Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UKDepartment of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UKDepartment of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UKDepartamento de Química Bio-Orgánica, IQOG, c/Juan de la Cierva 3, E-28006 Madrid, SpainDepartamento de Química Bio-Orgánica, IQOG, c/Juan de la Cierva 3, E-28006 Madrid, SpainDepartamento de Química Bio-Orgánica, IQOG, c/Juan de la Cierva 3, E-28006 Madrid, SpainDepartment of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UKThe protein kinase Mps1 (monopolar spindle 1) is an important regulator of the Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system of higher organisms that monitors the proper bipolar attachment of all chromosomes to the mitotic spindle during cell division. Defects in the catalytic activity and the transcription regulation of Mps1 are associated with genome instability, aneuploidy, and cancer. Moreover, multiple Mps1 missense and frameshift mutations have been reported in a wide range of types of cancer of different tissue origin. Due to these features, Mps1 arises as one promising drug target for cancer therapy. In this contribution, we developed a computational biology approach to study the dynamics of human Mps1 kinase interaction with isoflavones, a class of natural flavonoids, and compared their predicted mode of binding with that observed in the crystal structure of Mps1 in complex with reversine, a small-sized inhibitor of Mps1 and Aurora B kinases. We concluded that isoflavones define a chemical scaffold that can be used to develop new Mps1 inhibitors for the treatment of cancer associated with Mps1 amplification and aberrant chromosome segregation. In a broader context, the present report illustrates how modern chemoinformatics approaches can accelerate drug development in oncology.https://www.mdpi.com/1422-0067/23/22/14228Mps1cancerpoor prognosis tumoursflavonoid-like compoundsbioinformaticsmolecular docking |
| spellingShingle | Lauren Pugh Alisha Pancholi Priscila Celeste Purat Sandra Agudo-Alvarez Raúl Benito-Arenas Agatha Bastida Victor M. Bolanos-Garcia Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer International Journal of Molecular Sciences Mps1 cancer poor prognosis tumours flavonoid-like compounds bioinformatics molecular docking |
| title | Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer |
| title_full | Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer |
| title_fullStr | Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer |
| title_full_unstemmed | Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer |
| title_short | Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer |
| title_sort | computational biology dynamics of mps1 kinase molecular interactions with isoflavones reveals a chemical scaffold with potential to develop new therapeutics for the treatment of cancer |
| topic | Mps1 cancer poor prognosis tumours flavonoid-like compounds bioinformatics molecular docking |
| url | https://www.mdpi.com/1422-0067/23/22/14228 |
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