Bisindolylmaleimides New Ligands of CaM Protein
In the present study, we reported the interactions at the molecular level of a series of compounds called Bisindolylmaleimide, as potential inhibitors of the calmodulin protein. Bisindolylmaleimide compounds are drug prototypes derived from <i>Staurosporine</i>, an alkaloid with activity...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/21/7161 |
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| author | Alejandro Sosa-Peinado Karina Fructuoso-García L. X. Vásquez-Bochm Martin González-Andrade |
| author_facet | Alejandro Sosa-Peinado Karina Fructuoso-García L. X. Vásquez-Bochm Martin González-Andrade |
| author_sort | Alejandro Sosa-Peinado |
| collection | DOAJ |
| description | In the present study, we reported the interactions at the molecular level of a series of compounds called Bisindolylmaleimide, as potential inhibitors of the calmodulin protein. Bisindolylmaleimide compounds are drug prototypes derived from <i>Staurosporine</i>, an alkaloid with activity for cancer treatment. Bisindolylmaleimide compounds II, IV, VII, X, and XI, are proposed and reported as possible inhibitors of calmodulin protein for the first time. For the above, a biotechnological device was used (fluorescent biosensor <i>h</i>CaM M124C-<i>mBBr</i>) to directly determine binding parameters experimentally (<i>K</i><sub>d</sub> and stoichiometry) of these compounds, and molecular modeling tools (Docking, Molecular Dynamics, and Chemoinformatic Analysis) to carry out the theoretical studies and complement the experimental data. The results indicate that this compound binds to calmodulin with a <i>K</i><sub>d</sub> between 193–248 nM, an order of magnitude lower than most classic inhibitors. On the other hand, the theoretical studies support the experimental results, obtaining an acceptable correlation between the ΔG<sub>Experimental</sub> and ΔG<sub>Theoretical</sub> (r<sup>2</sup> = 0.703) and providing us with complementary molecular details of the interaction between the calmodulin protein and the Bisindolylmaleimide series. Chemoinformatic analyzes bring certainty to Bisindolylmaleimide compounds to address clinical steps in drug development. Thus, these results make these compounds attractive to be considered as possible prototypes of new calmodulin protein inhibitors. |
| first_indexed | 2024-03-09T18:49:22Z |
| format | Article |
| id | doaj.art-db8fc7bf4dd844b49828b720e16b8218 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T18:49:22Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-db8fc7bf4dd844b49828b720e16b82182023-11-24T05:59:37ZengMDPI AGMolecules1420-30492022-10-012721716110.3390/molecules27217161Bisindolylmaleimides New Ligands of CaM ProteinAlejandro Sosa-Peinado0Karina Fructuoso-García1L. X. Vásquez-Bochm2Martin González-Andrade3Laboratorio de Biosensores y Modelaje Molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, MexicoLaboratorio de Biosensores y Modelaje Molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, MexicoDepartamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, MexicoLaboratorio de Biosensores y Modelaje Molecular, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México 04510, MexicoIn the present study, we reported the interactions at the molecular level of a series of compounds called Bisindolylmaleimide, as potential inhibitors of the calmodulin protein. Bisindolylmaleimide compounds are drug prototypes derived from <i>Staurosporine</i>, an alkaloid with activity for cancer treatment. Bisindolylmaleimide compounds II, IV, VII, X, and XI, are proposed and reported as possible inhibitors of calmodulin protein for the first time. For the above, a biotechnological device was used (fluorescent biosensor <i>h</i>CaM M124C-<i>mBBr</i>) to directly determine binding parameters experimentally (<i>K</i><sub>d</sub> and stoichiometry) of these compounds, and molecular modeling tools (Docking, Molecular Dynamics, and Chemoinformatic Analysis) to carry out the theoretical studies and complement the experimental data. The results indicate that this compound binds to calmodulin with a <i>K</i><sub>d</sub> between 193–248 nM, an order of magnitude lower than most classic inhibitors. On the other hand, the theoretical studies support the experimental results, obtaining an acceptable correlation between the ΔG<sub>Experimental</sub> and ΔG<sub>Theoretical</sub> (r<sup>2</sup> = 0.703) and providing us with complementary molecular details of the interaction between the calmodulin protein and the Bisindolylmaleimide series. Chemoinformatic analyzes bring certainty to Bisindolylmaleimide compounds to address clinical steps in drug development. Thus, these results make these compounds attractive to be considered as possible prototypes of new calmodulin protein inhibitors.https://www.mdpi.com/1420-3049/27/21/7161biosensorscalmodulinbisindolylmaleimidesanti-CaM drugsdockingmolecular dynamic |
| spellingShingle | Alejandro Sosa-Peinado Karina Fructuoso-García L. X. Vásquez-Bochm Martin González-Andrade Bisindolylmaleimides New Ligands of CaM Protein Molecules biosensors calmodulin bisindolylmaleimides anti-CaM drugs docking molecular dynamic |
| title | Bisindolylmaleimides New Ligands of CaM Protein |
| title_full | Bisindolylmaleimides New Ligands of CaM Protein |
| title_fullStr | Bisindolylmaleimides New Ligands of CaM Protein |
| title_full_unstemmed | Bisindolylmaleimides New Ligands of CaM Protein |
| title_short | Bisindolylmaleimides New Ligands of CaM Protein |
| title_sort | bisindolylmaleimides new ligands of cam protein |
| topic | biosensors calmodulin bisindolylmaleimides anti-CaM drugs docking molecular dynamic |
| url | https://www.mdpi.com/1420-3049/27/21/7161 |
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