title: QSAR of estrogen receptor modulators: exploring selectivity requirements for ER(alpha) versus ER(beta) binding of tetrahydroisoquinoline derivatives using E-state and physicochemical parameters.
abstract: Considering importance of developing selective estrogen receptor modulators (SERMs), the present paper explores selectivity requirements of tetrahydroisoquinoline derivatives for binding with ER(alpha) versus ER(beta) receptors using E-state index and physicochemical parameters. The best model [n=21, Q(2)=0.512, R(a)(2)=0.613, R=0.819, F=11.6 (df 3,17)] for ER(alpha) binding data obtained from radioligand binding assay showed importance of C(1), C(15) and lipophilicity (logP) while the best model [n=21, Q(2)=0.768, R(a)(2)=0.796, R=0.904, F=40.1 (df 2,18)] for ER(beta) binding data showed importance of C(1) and molar refractivity (MR). While modeling ER(alpha)/ER(beta) selectivity [n=21, Q(2)=0.695, R(a)(2)=0.739, R=0.882, F=19.8 (df 3,17)], C(1), C(15) and molar refractivity were found to be significant contributors. The data obtained from cellular transcription assay were also modeled. In case of ER(alpha), the best equation involving E-state values of C(1) and C(14) and logP explained 62.1% of the variance while the best equation for ER(beta) involving E-state values of C(1) and C(15) and MR explained 64.6% of the variance of the response variable. In case of ER(alpha)/ER(beta) selectivity, the best equation involving E-state values of O(8), C(14) and N(27) showed 48.3% explained variance, which increased to 63.5% on deletion of single outlier. From the analysis it appears that the nitrogen atom of the aminoethoxyphenyl substituent and 6-hydroxy substituent of the tetrahydroisoquinoline nucleus play important roles for ER(alpha)/ER(beta) selectivity in addition to R(1) and R(2) substituents.
authors.affiliation: Department of Chemical Technology, University of Calcutta, 92 A P C Road, Kolkata 700 009, India.
authors.forename: Subhendu
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Achintya
authors.initials: A
authors.lastname: Saha
authors.forename: Kunal
authors.initials: K
authors.lastname: Roy
mesh_terms: D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000187:drug effects; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D044005:Tetrahydroisoquinolines