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论文类型：期刊论文

发表时间：2013-09-01

发表刊物：CHEMICAL RESEARCH IN TOXICOLOGY

收录刊物：SCIE、PubMed、Scopus

卷号：26

期号：9

页面范围：1340-1347

ISSN号：0893-228X

摘要：The molecular structures of many endocrine-disrupting chemicals (EDCs) contain groups that ionize under physiological pH conditions. It is unclear whether the neutral and ionic forms have different binding mechanisms with the macromolecular targets. We selected phenolic compounds and human transthyretin (hTTR) as a model system and employed molecular docking with quantum mechanics/molecular mechanics optimizations to probe the mechanisms. The binding patterns of ionizable ligands in hTTR crystal structures were also analyzed. We found that the anionic forms of the phenolic compounds bind stronger than the corresponding neutral forms with hTTR. Electrostatic and van de Waals interactions are the dominant forces for most of the anionic and neutral forms, respectively. Because of the dominant and orientational electrostatic interactions, the -O- groups point toward the entry port of the binding site. The aromatic rings of the compounds also form cation-pi interactions with the -NH3+ group of Lys 15 residues in hTTR Molecular descriptors were selected to characterize the interactions and construct a quantitative structure activity relationship model on the relative competing potency of chemicals with T-4 binding to hTTR It is concluded that the effects of ionization should not be neglected when constructing in silico models for screening of potential EDCs.