In Silico Investigation of Agonist Activity of a Structurally Diverse Set of Drugs to hPXR Using HM-BSM and HM-PNN

The human pregnane X receptor（hPXR） plays a critical role in the metabolism, transport and clearance of xenobiotics in the liver and intestine. The hPXR can be activated by a structurally diverse of drugs to initiate clinically relevant drug-drug interactions. In this article, in silico investigation was performed on a structurally diverse set of drugs to identify critical structural features greatly related to their agonist activity towards h PXR. Heuristic method（HM）-Best Subset Modeling（BSM） and HM-Polynomial Neural Networks（PNN） were utilized to develop the linear and non-linear quantitative structure-activity relationship models. The applicability domain（AD） of the models was assessed by Williams plot. Statistically reliable models with good predictive power and explain were achieved（for HM-BSM, r^2=0.881, q^2_（LOO）=0.797, q^2_（EXT）=0.674; for HM-PNN, r^2=0.882, q^2_（LOO）=0.856, q^2_（EXT）=0.655）. The developed models indicated that molecular aromatic and electric property, molecular weight and complexity may govern agonist activity of a structurally diverse set of drugs to h PXR.

Screening of agonistic activities against four nuclear receptors in wastewater treatment plants in Japan using a yeast two-hybrid assay

To assess the potential endocrine disruptive effects through multiple nuclear receptors （NRs）, especially non-steroidal NRs, in municipal wastewater, we examined the agonistic activities on four NRs （estrogen receptor α, thyroid hormone receptor α, retinoic acid receptor ct and retinoid X receptor α） of untreated and treated wastewater from municipal wastewater treatment plants （WWTPs） in Japan using a yeast two-hybrid assay. Investigation of the influent and effluent of seven WWTPs revealed that agonistic activities against steroidal and non-steroidal NRs were always detected in the influents and partially remained in the effluents. Further investigation of four WWTPs employing conventional activated sludge, pseudo-anoxic-oxic, anoxic-oxic and anaerobic-anoxic-oxic processes revealed that the ability to reduce the agonistic activity against each of the four NRs varies depending on the treatment process. These results indicated that municipal wastewater in Japan commonly contains endocrine disrupting chemicals that exert agonistic activities on steroidal and non-steroidal NRs, and that some of these chemicals are released into the natural aquatic environment. Although the results obtained in yeast assays suggested that measured levels of non-steroidal NR agonists in the effluent of WWTPs were not likely to cause any biological effect, further study is required to assess their possible risks in detail.

In vitro assessment of thyroid hormone receptor activity of four organophosphate esters

Previous animal experiments have implied that organophosphate esters（OPEs） have a disruption effect on the thyroid endocrine system. However, knowledge of the toxicological mechanism remains limited. In this study, the activities of four OPEs have been characterized against the thyroid hormone（TH） nuclear receptor（TR） using two in vitro models, with the aim of evaluating their toxicity mechanisms towards the TR. The results of a TH-dependent cell proliferation assay showed that tris（2-chloro-1-（chloromethyl）ethyl）phosphate（TDCPP） could induce cell growth, while the other three OPEs had no effect. The results of a luciferase reporter gene assay revealed that all four of the OPEs tested in the current study showed agonistic activity towards TRβ, with TDCPP being the most potent one. Moreover, molecular docking revealed that all the tested OPEs could fit into the ligand binding pocket of TRβ, with TDCPP binding more effectively than the other three OPEs. Taken together, these data suggest that OPEs might disrupt the thyroid endocrine system via a mechanism involving the activation of TR.

7,8-dihydroxyflavone,a small molecular TrkB agonist,is useful for treating various BDNF-implicated human disorders

Brain-derived neurotrophic factor(BDNF)regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB.It is a potential therapeutic target in numerous neurological,mental and metabolic disorders.However,the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application.To address this challenge,we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist.7,8-Dihydroxyflavone(7,8-DHF)is our first reported small molecular TrkB agonist,which has now been extensively validated in various biochemical and cellular systems.Though binding to the extracellular domain of TrkB,7,8-DHF triggers TrkB dimerization to induce the downstream signaling.Notably,7,8-DHF is orally bioactive that can penetrate the brain blood barrier(BBB)to exert its neurotrophic activities in the central nervous system.Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling.In this review,we summarize our current knowledge on the binding activity and specificity,structure-activity relationship,pharmacokinetic and metabolism,and the pre-clinical efficacy of 7,8-DHF against some human diseases.

The first examples of ilexgenin A hybrids as a new class of multi-potent,anti-platelet agents

Seventeen novel ilexgenin A hybrids（lA-aspirin） and（IA-NO）,as donor hybrids（IA-NO will release NO in vivo and function as NO donor）,were designed and synthesized in order to develop new multi-targeting agents for the treatment of platelet disorders.Their in vitro activities against ADP,AA and thrombin were evaluated.As a result,IA hybrids achieved substantial increases in the three tested pathways compared with IA.Encouragingly,the most potent hybrid compounds 6d and 14d displayed about 8-fold higher potency than aspirin,and 3-fold higher potency than the simultaneous administration of aspirin and IA in inhibiting ADP-induced aggregation with IC_（50） values of 0.15 mmol/L and 0.14 mmol/L,respectively. The results suggest these IA hybrids are good candidates for multi-target therapies,and especially,may be considered as promising ADP agonists.