PMID- 35782743
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 2001-0370 (Print)
IS  - 2001-0370 (Electronic)
IS  - 2001-0370 (Linking)
VI  - 20
DP  - 2022
TI  - Discrepancy in interactions and conformational dynamics of pregnane X receptor 
      (PXR) bound to an agonist and a novel competitive antagonist.
PG  - 3004-3018
LID - 10.1016/j.csbj.2022.06.020 [doi]
AB  - Pregnane X receptor (PXR) is a nuclear receptor with an essential role in 
      regulating drug metabolism genes. While the mechanism of action for 
      ligand-mediated PXR agonism is well-examined, its ligand-mediated inhibition or 
      antagonism is poorly understood. Here we employ microsecond timescale all-atom 
      molecular dynamics (MD) simulations to investigate how our newly identified dual 
      kinase and PXR inhibitor, compound 100, acts as a competitive PXR antagonist and 
      not as a full agonist. We study the PXR ligand binding domain conformational 
      changes associated with compound 100 and compare the results to the full agonist 
      SR12813, in presence and absence of the coactivator. Furthermore, we complement 
      our research by experimentally disclosing the effect of eight key-residue 
      mutations on PXR activation. Finally, simulations of P2X4 inhibitor (BAY-1797) in 
      complex with PXR, which shares an identical structural moiety with compound 100, 
      provide further insights to ligand-induced PXR behaviour. Our MD data suggests 
      ligand-specific influence on conformations of different PXR-LBD regions, 
      including alpha6 region, alphaAF-2, alpha1-alpha2', beta1'-alpha3 and beta1-beta1' loop. Our results provide 
      important insights on conformational behaviour of PXR and offers guidance how to 
      alleviate PXR agonism or to promote PXR antagonism.
CI  - (c) 2022 The Author(s).
FAU - Rashidian, Azam
AU  - Rashidian A
AD  - Department of Internal Medicine VIII, University Hospital Tuebingen, 
      Otfried-Muller-Strasse 14, Tuebingen DE 72076, Germany.
FAU - Mustonen, Enni-Kaisa
AU  - Mustonen EK
AD  - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and 
      University of Tuebingen, Tuebingen, Germany.
FAU - Kronenberger, Thales
AU  - Kronenberger T
AD  - Department of Internal Medicine VIII, University Hospital Tuebingen, 
      Otfried-Muller-Strasse 14, Tuebingen DE 72076, Germany.
AD  - Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical 
      Sciences, Eberhard-Karls-Universitat, Tuebingen, Auf der Morgenstelle 8, 
      Tuebingen 72076, Germany.
AD  - Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed 
      Tumor Therapies", University of Tuebingen, Tuebingen 72076, Germany.
AD  - Tuebingen Center for Academic Drug Discovery & Development (TuCAD2), Tuebingen 
      72076, Germany.
FAU - Schwab, Matthias
AU  - Schwab M
AD  - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and 
      University of Tuebingen, Tuebingen, Germany.
AD  - Departments of Clinical Pharmacology, and Pharmacy and Biochemistry, University 
      of Tuebingen, Tuebingen, Germany.
AD  - Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed 
      Tumor Therapies", University of Tuebingen, Tuebingen 72076, Germany.
FAU - Burk, Oliver
AU  - Burk O
AD  - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and 
      University of Tuebingen, Tuebingen, Germany.
FAU - Laufer, Stefan A
AU  - Laufer SA
AD  - Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical 
      Sciences, Eberhard-Karls-Universitat, Tuebingen, Auf der Morgenstelle 8, 
      Tuebingen 72076, Germany.
AD  - Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed 
      Tumor Therapies", University of Tuebingen, Tuebingen 72076, Germany.
AD  - Tuebingen Center for Academic Drug Discovery & Development (TuCAD2), Tuebingen 
      72076, Germany.
FAU - Pantsar, Tatu
AU  - Pantsar T
AD  - Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical 
      Sciences, Eberhard-Karls-Universitat, Tuebingen, Auf der Morgenstelle 8, 
      Tuebingen 72076, Germany.
AD  - School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 
      Yliopistonranta 1, Kuopio 70210, Finland.
LA  - eng
PT  - Journal Article
DEP - 20220613
PL  - Netherlands
TA  - Comput Struct Biotechnol J
JT  - Computational and structural biotechnology journal
JID - 101585369
PMC - PMC9218138
OTO - NOTNLM
OT  - BAY-1797 (PubChem CID: 124125214)
OT  - Molecular dynamics simulation
OT  - PXR ligand binding domain
OT  - Pregnane X receptor
OT  - SR12813 (PubChem CID: 446313)
COIS- The authors declare that they have no known competing financial interests or 
      personal relationships that could have appeared to influence the work reported in 
      this paper.
EDAT- 2022/07/06 06:00
MHDA- 2022/07/06 06:01
PMCR- 2022/06/13
CRDT- 2022/07/05 09:57
PHST- 2022/03/18 00:00 [received]
PHST- 2022/06/09 00:00 [revised]
PHST- 2022/06/09 00:00 [accepted]
PHST- 2022/07/05 09:57 [entrez]
PHST- 2022/07/06 06:00 [pubmed]
PHST- 2022/07/06 06:01 [medline]
PHST- 2022/06/13 00:00 [pmc-release]
AID - S2001-0370(22)00234-3 [pii]
AID - 10.1016/j.csbj.2022.06.020 [doi]
PST - epublish
SO  - Comput Struct Biotechnol J. 2022 Jun 13;20:3004-3018. doi: 
      10.1016/j.csbj.2022.06.020. eCollection 2022.