The Pregnane X Receptor (PXR) is a ligand-activated transcription factor belonging to the nuclear receptor family. PXR can bind diverse drugs and environmental toxicants with different binding modes, making it an intriguing target for drug discovery. Here we investigated the binding mechanism of the SR12813 ligand to elucidate the significant steps, from the ligand entrance pathway into the binding cavity, to the ligand-induced conformational changes, and to the exploration of its alternative binding geometries. We used the advanced Molecular Dynamics-based methods implemented in the BiKi suite and developed specific methodological approaches to overcome the complexity induced by the buried and flexible binding cavity. The adopted methods provided a full dynamic description of the binding event and allowed rationalization of the observed multiple binding modes. These results suggest that the same approach could be exploited for the study of other binding processes with similar characteristics.

Motta, S., Callea, L., Giani Tagliabue, S., & Bonati, L. (2018). Exploring the PXR ligand binding mechanism with advanced Molecular Dynamics methods. SCIENTIFIC REPORTS, 8(1), 1-12 [10.1038/s41598-018-34373-z].

Exploring the PXR ligand binding mechanism with advanced Molecular Dynamics methods

Motta, Stefano
Primo
;
Callea, Lara
Secondo
;
Giani Tagliabue, Sara
Penultimo
;
Bonati, Laura
Ultimo
2018

Abstract

The Pregnane X Receptor (PXR) is a ligand-activated transcription factor belonging to the nuclear receptor family. PXR can bind diverse drugs and environmental toxicants with different binding modes, making it an intriguing target for drug discovery. Here we investigated the binding mechanism of the SR12813 ligand to elucidate the significant steps, from the ligand entrance pathway into the binding cavity, to the ligand-induced conformational changes, and to the exploration of its alternative binding geometries. We used the advanced Molecular Dynamics-based methods implemented in the BiKi suite and developed specific methodological approaches to overcome the complexity induced by the buried and flexible binding cavity. The adopted methods provided a full dynamic description of the binding event and allowed rationalization of the observed multiple binding modes. These results suggest that the same approach could be exploited for the study of other binding processes with similar characteristics.
Articolo in rivista - Articolo scientifico
Scientifica
PXR, Ligand Binding, MD-Binding
English
Motta, S., Callea, L., Giani Tagliabue, S., & Bonati, L. (2018). Exploring the PXR ligand binding mechanism with advanced Molecular Dynamics methods. SCIENTIFIC REPORTS, 8(1), 1-12 [10.1038/s41598-018-34373-z].
Motta, S; Callea, L; Giani Tagliabue, S; Bonati, L
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/212289
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