Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
To find novel P-gp-inhibitors, a library of pregnane X receptor (PXR) ligands and the ZINC DrugsNow library were superimposed on the P-gp inhibitor (+)-pinoresinol (1) used as a query for a three-dimensional similarity search. After determining the TanimotoCombo index of similarity with 1, eight com...
| Autores: | , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | Argentina |
| Institución: | Consejo Nacional de Investigaciones Científicas y Técnicas |
| Repositorio: | CONICET Digital (CONICET) |
| Idioma: | inglés |
| OAI Identifier: | oai:ri.conicet.gov.ar:11336/95224 |
| Acceso en línea: | http://hdl.handle.net/11336/95224 |
| Access Level: | acceso abierto |
| Palabra clave: | DIETHYLSTILBESTROL DERIVATIVES MDR REVERSING AGENTS MOLECULAR DOCKING P-GLYCOPROTEIN PINORESINOL STRUCTURE-ACTIVITY RELATIONSHIP https://purl.org/becyt/ford/1.4 https://purl.org/becyt/ford/1 |
| Sumario: | To find novel P-gp-inhibitors, a library of pregnane X receptor (PXR) ligands and the ZINC DrugsNow library were superimposed on the P-gp inhibitor (+)-pinoresinol (1) used as a query for a three-dimensional similarity search. After determining the TanimotoCombo index of similarity with 1, eight compounds from the PXR library and two ZINC compounds were selected for biological evaluation. The P-gp inhibition study showed that compounds 7, 8, and 9 successfully increased intracellular doxorubicin (DOX) accumulation in the P-gp overexpressed Lucena 1 cells from 25, 12.5, and 6.25 μM, respectively. Among a series of analogues of 9, compounds 26–30 were shown to be active, with 26 and 27 causing a significant increase in DOX accumulation from 1.56 μM and rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 μM, respectively. Molecular modeling studies showed that both compounds bind to the P-gp at transmembrane helices (TMH) 4, 5, and 6, with 27 also showing contacts with TMH 3. |
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