dc.contributor.author | Perez Diaz, Noelia | |
dc.contributor.author | Lione, Lisa | |
dc.contributor.author | Hutter, Victoria | |
dc.contributor.author | Mackenzie, Louise Susan | |
dc.date.accessioned | 2021-03-25T15:00:21Z | |
dc.date.available | 2021-03-25T15:00:21Z | |
dc.date.issued | 2021-03-19 | |
dc.identifier.citation | Perez Diaz , N , Lione , L , Hutter , V & Mackenzie , L S 2021 , ' Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery ' , International Journal of Molecular Sciences (IJMS) , vol. 22 , no. 6 , 3158 . https://doi.org/10.3390/ijms22063158 | |
dc.identifier.issn | 1661-6596 | |
dc.identifier.uri | http://hdl.handle.net/2299/24169 | |
dc.description | © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/) | |
dc.description.abstract | Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepan-cies in understanding the complex role of PPARβ/δ in disease, having both anti‐ and pro‐effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ‐regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL‐6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L−165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL‐6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS‐induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARβ/δ agonists leads to a significant increase in Pdk−4 and Angptl−4 mRNA expression, which is significantly decreased in the presence of PPARβ/δ antagonists. Docking using computational chemistry methods indicates that PPARβ/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARβ/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co‐incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARβ/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARβ/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARβ/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production. | en |
dc.format.extent | 20 | |
dc.format.extent | 2256758 | |
dc.language.iso | eng | |
dc.relation.ispartof | International Journal of Molecular Sciences (IJMS) | |
dc.subject | Docking | |
dc.subject | GSK3787 | |
dc.subject | GW0742 | |
dc.subject | Gene transcription | |
dc.subject | Inflammation | |
dc.subject | Lipopolysaccharide (LPS) | |
dc.subject | Lung | |
dc.subject | Molecular docking | |
dc.subject | Nuclear receptor | |
dc.subject | PPARβ/δ | |
dc.subject | Pulmonary artery | |
dc.subject | Inflammation Mediators/metabolism | |
dc.subject | Benzamides/chemistry | |
dc.subject | Molecular Conformation | |
dc.subject | Male | |
dc.subject | PPAR-beta/agonists | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Nitric Oxide/metabolism | |
dc.subject | Lipopolysaccharides/adverse effects | |
dc.subject | Pulmonary Artery/drug effects | |
dc.subject | Binding Sites | |
dc.subject | Thiazoles/chemistry | |
dc.subject | Gene Expression | |
dc.subject | Rats | |
dc.subject | Molecular Dynamics Simulation | |
dc.subject | Sulfones/chemistry | |
dc.subject | PPAR delta/agonists | |
dc.subject | Animals | |
dc.subject | Biomarkers | |
dc.subject | Protein Binding | |
dc.subject | Ligands | |
dc.subject | Molecular Docking Simulation | |
dc.subject | Molecular Biology | |
dc.subject | Spectroscopy | |
dc.subject | Catalysis | |
dc.subject | Inorganic Chemistry | |
dc.subject | Computer Science Applications | |
dc.subject | Physical and Theoretical Chemistry | |
dc.subject | Organic Chemistry | |
dc.title | Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery | en |
dc.contributor.institution | School of Life and Medical Sciences | |
dc.contributor.institution | Centre for Health Services and Clinical Research | |
dc.contributor.institution | Basic and Clinical Science Unit | |
dc.contributor.institution | TRP Ion channels | |
dc.contributor.institution | Department of Clinical, Pharmaceutical and Biological Science | |
dc.contributor.institution | Airway Group | |
dc.contributor.institution | Pharmaceutics | |
dc.contributor.institution | Centre for Research into Topical Drug Delivery and Toxicology | |
dc.contributor.institution | Centre for Research in Mechanisms of Disease and Drug Discovery | |
dc.description.status | Peer reviewed | |
dc.identifier.url | http://www.scopus.com/inward/record.url?scp=85102699697&partnerID=8YFLogxK | |
rioxxterms.versionofrecord | 10.3390/ijms22063158 | |
rioxxterms.type | Journal Article/Review | |
herts.preservation.rarelyaccessed | true | |