A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature
Abstract The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/33a551dcc5004dd0b9cac26fa715e9a5 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:33a551dcc5004dd0b9cac26fa715e9a5 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:33a551dcc5004dd0b9cac26fa715e9a52021-12-02T15:05:06ZA combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature10.1038/s41598-017-08404-02045-2322https://doaj.org/article/33a551dcc5004dd0b9cac26fa715e9a52017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08404-0https://doaj.org/toc/2045-2322Abstract The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico – in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied. The virtual hits were tested for the inhibition of recombinant human CYP2D6 in a bioluminescence-based assay. By controlling for unspecific interferences of the test compounds with the detection reaction, the number of false positives were reduced. The success rate of the reported workflow was 76%, as most of the candidates identified in the in silico approach were able to inhibit CYP2D6 activity. In summary, the workflow presented here is a suitable and cost-efficient strategy for the discovery of new CYP2D6 inhibitors with natural product libraries.Johannes HochleitnerMuhammad AkramMartina UeberallRohan A. DavisBirgit WaltenbergerHermann StuppnerSonja SturmFlorian UeberallJohanna M. GostnerDaniela SchusterNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Johannes Hochleitner Muhammad Akram Martina Ueberall Rohan A. Davis Birgit Waltenberger Hermann Stuppner Sonja Sturm Florian Ueberall Johanna M. Gostner Daniela Schuster A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature |
| description |
Abstract The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico – in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied. The virtual hits were tested for the inhibition of recombinant human CYP2D6 in a bioluminescence-based assay. By controlling for unspecific interferences of the test compounds with the detection reaction, the number of false positives were reduced. The success rate of the reported workflow was 76%, as most of the candidates identified in the in silico approach were able to inhibit CYP2D6 activity. In summary, the workflow presented here is a suitable and cost-efficient strategy for the discovery of new CYP2D6 inhibitors with natural product libraries. |
| format |
article |
| author |
Johannes Hochleitner Muhammad Akram Martina Ueberall Rohan A. Davis Birgit Waltenberger Hermann Stuppner Sonja Sturm Florian Ueberall Johanna M. Gostner Daniela Schuster |
| author_facet |
Johannes Hochleitner Muhammad Akram Martina Ueberall Rohan A. Davis Birgit Waltenberger Hermann Stuppner Sonja Sturm Florian Ueberall Johanna M. Gostner Daniela Schuster |
| author_sort |
Johannes Hochleitner |
| title |
A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature |
| title_short |
A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature |
| title_full |
A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature |
| title_fullStr |
A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature |
| title_full_unstemmed |
A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature |
| title_sort |
combinatorial approach for the discovery of cytochrome p450 2d6 inhibitors from nature |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/33a551dcc5004dd0b9cac26fa715e9a5 |
| work_keys_str_mv |
AT johanneshochleitner acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT muhammadakram acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT martinaueberall acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT rohanadavis acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT birgitwaltenberger acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT hermannstuppner acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT sonjasturm acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT florianueberall acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT johannamgostner acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT danielaschuster acombinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT johanneshochleitner combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT muhammadakram combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT martinaueberall combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT rohanadavis combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT birgitwaltenberger combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT hermannstuppner combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT sonjasturm combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT florianueberall combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT johannamgostner combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature AT danielaschuster combinatorialapproachforthediscoveryofcytochromep4502d6inhibitorsfromnature |
| _version_ |
1718388946243682304 |