Calculations of the binding free energies of the Comprehensive in vitro Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channels
The evaluation of the inhibitory activities of drugs on multiple cardiac ion channels is required for the accurate assessment of proarrhythmic risks. Moreover, the in silico prediction of such inhibitory activities of drugs on cardiac channels can improve the efficiency of the drug-development proce...
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| Format: | Article |
| Language: | English |
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The Biophysical Society of Japan
2023-04-01
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| Series: | Biophysics and Physicobiology |
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| Online Access: | https://doi.org/10.2142/biophysico.bppb-v20.0016 |
| _version_ | 1797797077994962944 |
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| author | Tatsuki Negami Tohru Terada |
| author_facet | Tatsuki Negami Tohru Terada |
| author_sort | Tatsuki Negami |
| collection | DOAJ |
| description | The evaluation of the inhibitory activities of drugs on multiple cardiac ion channels is required for the accurate assessment of proarrhythmic risks. Moreover, the in silico prediction of such inhibitory activities of drugs on cardiac channels can improve the efficiency of the drug-development process. Here, we performed molecular docking simulations to predict the complex structures of 25 reference drugs that were proposed by the Comprehensive in vitro Proarrhythmia Assay consortium using two cardiac ion channels, the human ether-a-go-go-related gene (hERG) potassium channel and human NaV1.5 (hNaV1.5) sodium channel, with experimentally available structures. The absolute binding free energy (ΔGbind) values of the predicted structures were calculated by a molecular dynamics-based method and compared with the experimental half-maximal inhibitory concentration (IC50) data. Furthermore, the regression analysis between the calculated values and negative of the common logarithm of the experimental IC50 values (pIC50) revealed that the calculated values of four and ten drugs deviated significantly from the regression lines of the hERG and hNaV1.5 channels, respectively. We reconsidered the docking poses and protonation states of the drugs based on the experimental data and recalculated their ΔGbind values. Finally, the calculated ΔGbind values of 24 and 19 drugs correlated with their experimental pIC50 values (coefficients of determination=0.791 and 0.613 for the hERG and hNaV1.5 channels, respectively). Thus, the regression analysis between the calculated ΔGbind and experimental IC50 data ensured the realization of an increased number of reliable complex structures. |
| first_indexed | 2024-03-13T03:42:43Z |
| format | Article |
| id | doaj.art-8bc6dbb23ca5410a8bed9525667a8dc0 |
| institution | Directory Open Access Journal |
| issn | 2189-4779 |
| language | English |
| last_indexed | 2024-03-13T03:42:43Z |
| publishDate | 2023-04-01 |
| publisher | The Biophysical Society of Japan |
| record_format | Article |
| series | Biophysics and Physicobiology |
| spelling | doaj.art-8bc6dbb23ca5410a8bed9525667a8dc02023-06-23T05:14:56ZengThe Biophysical Society of JapanBiophysics and Physicobiology2189-47792023-04-012010.2142/biophysico.bppb-v20.0016Calculations of the binding free energies of the Comprehensive in vitro Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channelsTatsuki Negami0Tohru Terada1Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, JapanDepartment of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, JapanThe evaluation of the inhibitory activities of drugs on multiple cardiac ion channels is required for the accurate assessment of proarrhythmic risks. Moreover, the in silico prediction of such inhibitory activities of drugs on cardiac channels can improve the efficiency of the drug-development process. Here, we performed molecular docking simulations to predict the complex structures of 25 reference drugs that were proposed by the Comprehensive in vitro Proarrhythmia Assay consortium using two cardiac ion channels, the human ether-a-go-go-related gene (hERG) potassium channel and human NaV1.5 (hNaV1.5) sodium channel, with experimentally available structures. The absolute binding free energy (ΔGbind) values of the predicted structures were calculated by a molecular dynamics-based method and compared with the experimental half-maximal inhibitory concentration (IC50) data. Furthermore, the regression analysis between the calculated values and negative of the common logarithm of the experimental IC50 values (pIC50) revealed that the calculated values of four and ten drugs deviated significantly from the regression lines of the hERG and hNaV1.5 channels, respectively. We reconsidered the docking poses and protonation states of the drugs based on the experimental data and recalculated their ΔGbind values. Finally, the calculated ΔGbind values of 24 and 19 drugs correlated with their experimental pIC50 values (coefficients of determination=0.791 and 0.613 for the hERG and hNaV1.5 channels, respectively). Thus, the regression analysis between the calculated ΔGbind and experimental IC50 data ensured the realization of an increased number of reliable complex structures.https://doi.org/10.2142/biophysico.bppb-v20.0016hergnav1.5dockingbinding free energymolecular dynamics |
| spellingShingle | Tatsuki Negami Tohru Terada Calculations of the binding free energies of the Comprehensive in vitro Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channels Biophysics and Physicobiology herg nav1.5 docking binding free energy molecular dynamics |
| title | Calculations of the binding free energies of the Comprehensive in vitro Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channels |
| title_full | Calculations of the binding free energies of the Comprehensive in vitro Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channels |
| title_fullStr | Calculations of the binding free energies of the Comprehensive in vitro Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channels |
| title_full_unstemmed | Calculations of the binding free energies of the Comprehensive in vitro Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channels |
| title_short | Calculations of the binding free energies of the Comprehensive in vitro Proarrhythmia Assay (CiPA) reference drugs to cardiac ion channels |
| title_sort | calculations of the binding free energies of the comprehensive in vitro proarrhythmia assay cipa reference drugs to cardiac ion channels |
| topic | herg nav1.5 docking binding free energy molecular dynamics |
| url | https://doi.org/10.2142/biophysico.bppb-v20.0016 |
| work_keys_str_mv | AT tatsukinegami calculationsofthebindingfreeenergiesofthecomprehensiveinvitroproarrhythmiaassaycipareferencedrugstocardiacionchannels AT tohruterada calculationsofthebindingfreeenergiesofthecomprehensiveinvitroproarrhythmiaassaycipareferencedrugstocardiacionchannels |