Table of Content

25 July 2018, Volume 27 Issue 7

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Original articles

Designing natural product-like virtual libraries using deep molecule generative models

Yibo Li, Xin Zhou, Zhenming Liu, Liangren Zhang

2018, 27(7):  451-459.  DOI: 10.5246/jcps.2018.07.046

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Natural products (NPs) have long been recognized as a valuable resource for drug discovery, and bringing NP-related features to virtual libraries is believed to be an effective way to increase the coverage of druggable chemical space. Here, deep learning-based molecule generative model, which is a recent technique in de novo molecule design, was applied to generate virtual libraries with NP-like properties. Results demonstrated that the model was effective in generating molecules that highly resemble NPs. Moreover, the model was also found to be capable of generating NP-like molecules that were also easy to synthesize, significantly increasing the practical value of the compound library.



Development of palladium-catalyzed Suzuki carbonylation reaction without external ligand and its application in modification of novel series of α7 nAChR PAMs

Ying Meng, Wenxing Zou, Zongze Huang, Xintong Wang, Wenxuan Jiao, Wenjun Xie, Xiling Bian, KeWei Wang, Qi Sun

2018, 27(7):  460-468.  DOI: 10.5246/jcps.2018.07.047

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Palladium-catalyzed Suzuki carbonylation with CHCl₃ as carbonylative reagent was realized without external ligands. Different substituted benzophenones were explored via the coupling reaction of aryl iodides, arylboronic acids and CHCl₃ as a CO surrogate in moderate to good yields. This method was also successfully applied to the structure modification of α7 nicotinic acetylcholine receptor positive allosteric modulators (α7 nAChR PAMs) based on the preliminary structure-activity relationship. 



Similar pyridinone compounds with different activities of anti-HIV-1 reverse transcriptase

Yunqi Liu, Xixi Li, Xiaodong Dou, Chao Tian, Zhili Zhang, Junyi Liu, Xiaowei Wang

2018, 27(7):  469-477.  DOI: 10.5246/jcps.2018.07.048

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Among the structurally diverse NNRTIs, pyridinone scaffolds demonstrate high potency against HIV-1 wild type and drug-resistant strains. During the optimization of our pyridinone compound 1 (LAM-trans),we found that the introduction of the N atoms in the C-4 position could dramatically improve the water solubility (7b), whereas protonation of the piperidine N atom resulted in a decrease in its hydrophobic interaction with the binding pocket. In particular, protonation altered the orientation of the alicyclic rings in the hydrophobic pocket, thus impeding the formation of key halogen bond and eventually leading to a huge change in anti-HIV-1 RT activity. These results provided theoretical and experimental basis for the subsequent structural modification of pyridinone compounds.



Construction of a Caco-2/EAhy926 cell tandem compound model and its application in mechanism study of nanoparticle transcytosis

AnPu Yang, Bei Wei, Jiafang Song, Xiangfu Guo, Yuxi Cheng, Bing He, Hua Zhang, Xueqing Wang, Qiang Zhang

2018, 27(7):  478-489.  DOI: 10.5246/jcps.2018.07.049

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Based on the physiological structure of the intestine, a Caco-2/EAhy926 tandem compound model was constructed in order to simulate the intestinal-vascular barrier. This model was applied in the study of transcytosis of nanoparticles, and it was compared with the traditional intestinal cell model in the whole study. Briefly, Fe₃O₄ nanoparticles with a size about 30 nm were used as model nanoparticles, which remained steady during transcytosis. The nanoparticles hardly had cytotoxicity to Caco-2 cells and EAhy926 cells within the incubation concentrations. The cell tandem model was established by connecting upper Caco-2 monolayer and lower EAhy926 monolayer. Based on the FD4 permeability or TEER, all cell models remained integrity within certain period of culture time. The expression of Claudin-4 or VE Cadherin demonstrated the presence of tight junctions. The intact morphology of microfilament F-actin indicated the favorable intracellular connection. It was found that the two-layer cell tandem model created a bigger barrier for the transcytosis of FD4 than Caco-2 and EAhy926 monolayer models, and the translocation of Fe₃O₄ nanoparticles showed a similar pattern. Interestingly, we found that the main barrier of tandem model for nanoparticles was caused by the upper Caco-2 cell monolayer, while the lower layer of EAhy926 monolayer remained high permeability. Generally, the cell tandem compound model established here enabled us to evaluate the impact of both intestinal epithelial and endothelial layer on transcytosis, and it might provide a novel approach to study bio-nano interaction in the intestine.



Preparation and characterization of intestinal transporter-targeted polymeric micelles

Chuyu He, Yao Jin, Yunqiang Deng, Yang Zou, Shidi Han, Chuhang Zhou, Yuanhang Zhou, Xinru Li, Yanxia Zhou, Yan Liu

2018, 27(7):  490-497.  DOI: 10.5246/jcps.2018.07.050

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The intestinal epithelium is the main barrier to the oral delivery of poorly water-soluble drugs. Based on the specific transporters expressed on the apical membrane of the intestinal epithelium, novel polymer micelles targeting to the organic cation transporter 2 (OCTN2) were constructed by combining carnitine conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (Car-PEOz-PLA) with monomethoxy poly(ethylene glycol)-poly(D,L-lactide) (mPEG-PLA). The structure of the synthesized Car-PEOz-PLA was confirmed by ¹H NMR, TLC and ammonium reineckate precipitation reaction, and the number-average molecular weight determined by GPC was 7260 g/mol with a low PDI of 1.44. Coumarin 6-loaded carnitine modified polymeric micelles prepared by film hydration method were characterized to have a nano-scaled size of about 31 nm in diameter, uniform spherical morphology, high drug loading content of 0.098%±0.03% and encapsulation efficiency of 92.67%±2.80%. Moreover, the carnitine-modified micelles exhibited the similar in vitro release behavior in SGF and SIF, and evidently enhanced intestinal absorption of poorly water-soluble agent. Therefore, the designed OCTN2-targeted micelles might have a promising potential for oral delivery of poorly water-soluble drugs.



Acetaminophen-induced hepatotoxicity in rats is correlated with the accumulation of bile acids: an underlying mechanism

Yongwen Jin, Zhi Rao, Yanfang Wu, Guoqiang Zhang, Axi Shi, Yuhui Wei, Xin’an Wu

2018, 27(7):  498-509.  DOI: 10.5246/jcps.2018.07.051

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In the present study, we aimed to investigate the underlying mechanism of acetaminophen (APAP)-induced hepatotoxicityby measuring the expression levels of liver transporters and concentrations of bile acids (BAs) in rat plasma and liver. SD rats (42)were randomly assigned into six groups, including 6-h control group, APAP 6-h group, 12-h control group, APAP 12-h group, 24-h control group and APAP 24-h group. The estimation study of BAs in plasma and liver was performed on LC-MS/MS.The levels of bile salt export pump (Bsep), multidrug resistant protein 2 (Mrp2), multidrug resistant protein 4 (Mrp4), Na⁺/taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) in the liver were analyzed by Western blotting analysis. Compared with the corresponding control groups, no difference was found in the BA levels and the expressions of BA transporters in the plasma and liver after 6 h of APAP administration. While BA levels were significantly decreased in the plasma and increased in the liver after 12 h of APAP administration (P<0.05); and the expressions of Bsep and Mrp2 were significantly reduced (P<0.05). After 24 h of APAP administration, BA levels were both greatly increased in the plasma and liver (P<0.05); and the expressions of Mrp4 and Oatp2 were significantly decreased (P<0.05). In response to over-dose APAP, Bsep, Mrp2, Mrp4 and Oatp2 levels were reduced at different time points, causing the accumulation of BAs, and such accumulation may ultimately lead to the severe liver injury, which could be an underlying mechanism of the APAP-induced hepatotoxicity. 



Drug administration and clinical pharmacy column

Empirical methods in studying the effect of pharmaceutical policies

Jing Chen, Ting Yin, Bin Jiang

2018, 27(7):  510-516.  DOI: 10.5246/jcps.2018.07.052

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Healthcare policies are often evaluated using empirical analysis methods. In this study, we summarized the hypothesis test, segmented regression analysis of interrupted time series, autoregressive integrated moving average model, difference in difference model, pooled regression model, fixed effect model, random effect model, propensity score matching method, cost-benefit analysis, and cost-effectiveness analysis. We also established a flow chart to demonstrate the process of selection of empirical analysis methods based on the purpose of policy evaluation, whether there is a control group, the type of data, and whether the data is linear.