title: Molecular determinants of thyroid hormone receptor selectivity in a series of phosphonic acid derivatives: 3D-QSAR analysis and molecular docking.
abstract: A mathematical study was performed on a set of phosphonic acid derivatives that are substrates for thyroid hormone receptor β (TRβ) and thyroid hormone receptor α (TRα), three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were employed to investigate the structural requirements for this series of compounds with improved activity. Some descriptors were also employed to significantly improve the performance of the derived models. The CoMFA model for TRβ exhibited Rcv(2) of 0.612, Rpred(2) of 0.7218, whereas CoMSIA model showed Rcv(2) of 0.621, R(2)pred of 0.7358; the CoMFA model for TRα displayed Rcv(2) of 0.678, Rpred(2) of 0.6424, and the CoMSIA model had Rcv(2) of 0.671, Rpred(2) of 0.6932, which indicate that the constructed models are statistically significant. The derived contour maps further pointed out the regions where interactive fields may influence the activity. In order to validate the QSAR models and explore the origin of the selectivity at the amino acid level, molecular docking was developed, and the results indicate that Arg282, Arg320, Asn331, Gly332, Thr329 and His435 for TRβ, but Ala225, Arg228, Met259, Arg262 and His381 for TRα, respectively are important residues. The information obtained from the QSAR models can be used in the design of more potent TR agonists.
authors.affiliation: The State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Shi
authors.affiliation: The State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China. Electronic address: lgw@jiangnan.edu.cn.
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: Le
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010757:Phosphorous Acids / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D010757:Phosphorous Acids; D011988:Receptors, Thyroid Hormone
keywords: CoMFA; CoMSIA; Molecular docking; TRα; TRβ