Scaffold-Based Pan-Agonist Design for the PPARα, PPARβ and PPARγ Receptors 英文参考文献.docVIP

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Scaffold-Based Pan-Agonist Design for the PPARα, PPARβ and PPARγ Receptors 英文参考文献.doc

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Scaffold-Based Pan-Agonist Design for the PPARα, PPARβ and PPARγ Receptors 英文参考文献

Scaffold-BasedPan-AgonistDesignforthePPARa,PPARb andPPARcReceptors Li-SongZhang1.,Shu-QingWang1.,Wei-RenXu2,Run-LingWang1*,Jing-FangWang3,4* 1TianjinKeyLaboratoryonTechnologiesEnablingDevelopmentofClinicalTherapeuticsandDiagnostics(Theranostics),SchoolofPharmacy,TianjinMedicalUniversity, Tianjin,China,2TianjinInstituteofPharmaceuticalResearch(TIPR),Tianjin,China,3KeyLaboratoryofSystemsBiomedicine(MinistryofEducation),ShanghaiCenterfor SystemsBiomedicine,ShanghaiJiaoTongUniversity,Shanghai,China,4ShanghaiCenterforBioinformationTechnology,Shanghai,China Abstract Asimportantmembersofnuclearreceptorsuperfamily,Peroxisome proliferator-activatedreceptors(PPAR)playessential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARa, PPARb and PPARc, all of which have been treated as attractive targets for developingdrugstotreattype2diabetes.Duetotheundesirableside-effects,manyPPARagonistsincludingPPARa/cand PPARb/cdualagonistsarestoppedbyUSFDAintheclinicaltrials.Analternativestrategyistodesignnovelpan-agonist thatcansimultaneouslyactivatePPARa,PPARbandPPARc.Undersuchanidea,inthecurrentstudyweadoptedthecore hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608.Itwasobservedbythedockingproceduresandmoleculardynamicssimulationsthatthecompoundsgenerated bythecorehoppingandglidedockingnotonlypossessed thesimilarfunctionsastheoriginalLY465608compoundto activatePPARa,PPARbandPPARcreceptors,butalsohadmorefavorableconformationforbindingtothePPARreceptors. The additional absorption, distribution, metabolism and excretion (ADME) predictions showed that the 7 compounds (especiallyCpd#1)holdhighpotentialtobenovelleadcompoundsforthePPARpan-agonist.Ourfindingscanprovide anewstrategyorusefulinsightsfordesigningtheeffectivepan-agonistsagainstthetype2diabetes. Citation: Zhang L-S, Wang S-Q, Xu W-R, Wang R-L, Wan