Probing the origins of aromatase inhibitory activity of disubstituted coumarins via QSAR and molecular docking

dc.contributor.authorWorachartcheewan, Apilak
dc.contributor.authorSuvannang, Naravut
dc.contributor.authorPrachayasittikul, Supaluk
dc.contributor.authorPrachayasittikul, Virapong
dc.contributor.authorNantasenamat, Chanin
dc.date.accessioned2015-04-20T13:00:57Z
dc.date.available2015-04-20T13:00:57Z
dc.date.issued2014-12-08
dc.description.abstractThis study investigated the quantitative structure-activity relationship (QSAR) of imidazole derivatives of 4,7-disubstituted coumarins as inhibitors of aromatase, a potential therapeutic protein target for the treatment of breast cancer. Herein, a series of 3,7- and 4,7-disubstituted coumarin derivatives (1-34) with R1 and R2 substituents bearing aromatase inhibitory activity were modeled as a function of molecular and quantum chemical descriptors derived from low-energy conformer geometrically optimized at B3LYP/6-31G(d) level of theory. Insights on origins of aromatase inhibitory activity was afforded by the computed set of 7 descriptors comprising of F10[N-O], Inflammat-50, Psychotic-80, H-047, BELe1, B10[C-O] and MAXDP. Such significant descriptors were used for QSAR model construction and results indicated that model 4 afforded the best statistical performance. Good predictive performance were achieved as verified from the internal (comprising the training and the leave-one-out cross-validation (LOO-CV) sets) and external sets affording the following statistical parameters: R2Tr = 0.9576 and RMSETr = 0.0958 for the training set; Q2CV = 0.9239 and RMSECV = 0.1304 for the LOO-CV set as well as Q2Ext = 0.7268 and RMSEExt = 0.2927 for the external set. Significant descriptors showed correlation with functional substituents, particularly, R1 in governing high potency as aromatase inhibitor. Molecular docking calculations suggest that key residues interacting with the coumarins were predominantly lipophilic or non-polar while a few were polar and positively-charged. Findings illuminated herein serve as the impetus that can be used to rationally guide the design of new aromatase inhibitors.en
dc.identifier.issn1611-2156
dc.identifier.urihttp://hdl.handle.net/2003/34007
dc.identifier.urihttp://dx.doi.org/10.17877/DE290R-7420
dc.language.isoen
dc.relation.ispartofseriesEXCLI Journal ; Vol. 13, 2014en
dc.subjectCoumarinen
dc.subjectaromataseen
dc.subjectaromatase inhibitor,en
dc.subjectQSARen
dc.subjectdata miningen
dc.subjectmolecular dockingen
dc.subject.ddc610
dc.titleProbing the origins of aromatase inhibitory activity of disubstituted coumarins via QSAR and molecular dockingen
dc.typeText
dc.type.publicationtypearticle
dcterms.accessRightsopen access
eldorado.dnb.zdberstkatid2132560-1

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