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dc.contributor.authorPerez Diaz, Noelia
dc.contributor.authorLione, Lisa
dc.contributor.authorHutter, Victoria
dc.contributor.authorMackenzie, Louise Susan
dc.date.accessioned2021-03-25T15:00:21Z
dc.date.available2021-03-25T15:00:21Z
dc.date.issued2021-03-19
dc.identifier.citationPerez 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 , vol. 22 , no. 6 , 3158 . https://doi.org/10.3390/ijms22063158
dc.identifier.issn1422-0067
dc.identifier.otherPURE: 21895034
dc.identifier.otherPURE UUID: 4950cb76-9290-4100-9e74-ef9a16836499
dc.identifier.otherScopus: 85102699697
dc.identifier.otherPubMed: 33808880
dc.identifier.urihttp://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.abstractPeroxisome 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.extent20
dc.language.isoeng
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.subjectDocking
dc.subjectGSK3787
dc.subjectGW0742
dc.subjectGene transcription
dc.subjectInflammation
dc.subjectLipopolysaccharide (LPS)
dc.subjectLung
dc.subjectMolecular docking
dc.subjectNuclear receptor
dc.subjectPPARβ/δ
dc.subjectPulmonary artery
dc.subjectInflammation Mediators/metabolism
dc.subjectBenzamides/chemistry
dc.subjectMolecular Conformation
dc.subjectMale
dc.subjectPPAR-beta/agonists
dc.subjectStructure-Activity Relationship
dc.subjectNitric Oxide/metabolism
dc.subjectLipopolysaccharides/adverse effects
dc.subjectPulmonary Artery/drug effects
dc.subjectBinding Sites
dc.subjectThiazoles/chemistry
dc.subjectGene Expression
dc.subjectRats
dc.subjectMolecular Dynamics Simulation
dc.subjectSulfones/chemistry
dc.subjectPPAR delta/agonists
dc.subjectAnimals
dc.subjectBiomarkers
dc.subjectProtein Binding
dc.subjectLigands
dc.subjectMolecular Docking Simulation
dc.subjectMolecular Biology
dc.subjectSpectroscopy
dc.subjectCatalysis
dc.subjectInorganic Chemistry
dc.subjectComputer Science Applications
dc.subjectPhysical and Theoretical Chemistry
dc.subjectOrganic Chemistry
dc.titleCo-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Arteryen
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionDepartment of Clinical and Pharmaceutical Sciences
dc.contributor.institutionCentre for Health Services and Clinical Research
dc.contributor.institutionBasic and Clinical Science Unit
dc.contributor.institutionTRP Ion channels
dc.contributor.institutionAgriculture, Food and Veterinary Sciences
dc.contributor.institutionDepartment of Clinical, Pharmaceutical and Biological Science
dc.contributor.institutionAirway Group
dc.contributor.institutionPharmaceutics
dc.contributor.institutionCentre for Research into Topical Drug Delivery and Toxicology
dc.description.statusPeer reviewed
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85102699697&partnerID=8YFLogxK
rioxxterms.versionVoR
rioxxterms.versionofrecordhttps://doi.org/10.3390/ijms22063158
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue


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