Determination of structure-activity relationships between fentanyl analogs and human μ-opioid receptors based on active binding site models

Fentanyl is a potent and widely used clinical narcotic analgesic, as well as a highly selective IJ-opioid agonist. The present study established a homologous model of the human μ-opioid receptor; an intercomparison of three types of μ-opioid receptor protein sequence homologous rates was made. The secondary receptor structure was predicted, the model reliability was assessed and verified using the Ramachandran plot and ProTab analysis. The predictive ability of the CoMFA model was further validated using an external test set. Using the Surflex-Dock program, a series of fentanyl analog molecules were docked to the receptor, the calculation results from Biopolymer/SitelD showed that the receptor had a deep binding area situated in the extracellular side of the transmembrane domains （TM） among TM3, TM5, TM6, and TMT. Results suggested that there might be 5 active areas in the receptor. The important residues were Asp147, Tyr148, and Tyr149 in TM3, Trp293, and His297 in TM6, and Trp318, His319, Ile322, and Tyr326 in TM7, which were located at the 5 active areas. The best fentanyl docking orientation position was the piperidine ring, which was nearly perpendicular to the membrane surface in the 7 TM domains. Molecular dynamic simulations were applied to evaluate potential relationships between ligand conformation and fentanyl substitution.

Three-dimensional pharmacophore screening for fentanyl derivatives

Fentanyl is a highly selective u-opioid receptor agonist with high analgesic activity. Three-dimensional pharmacophore models were built from a set of 50 fentanyl derivatives. These were employed to elucidate ligand-receptor interactions using information derived only from the ligand structure to identify new potential lead compounds. The present studies demonstrated that three hydrophobic regions, one positive ionizable region and two hydrogen bond acceptor region sites located on the molecule seem to be essential for analgesic activity. The results of the comparative molecular field analysis model suggested that both steric and electrostatic interactions play important roles. The contributions from steric and electrostatic fields for the model were 0.621 and 0.379, respectively. The pharmacophore model provides crucial information about how well the common features of a subject molecule overlap with the hypothesis model, which is very valuable for designing and optimizing new active structures.

一种静态的编译器重复缺陷报告识别方法

编译器缺陷报告在编译器质量保证中具有重要作用,而重复缺陷报告往往带来不必要的人力、时间等资源浪费.为了识别编译器重复缺陷报告,本文提出了一种静态的重复缺陷报告识别方法IdenDup.该方法可以有效解决两个场景下的重复缺陷报告问题,即模糊测试(fuzz testing)所产生的缺陷报告和缺陷管理系统中不同来源的缺陷报告.具体来说,IdenDup利用缺陷报告中静态文本和程序特征来识别重复缺陷报告,其中程序特征包括程序词法、语法,以及本文首次提出的数据流特征.特别地,程序数据流特征指的是程序中变量使用路径(变量使用方式及使用方式的顺序)特征.之后,我们使用C语言的两个主流编译器GCC和LLVM作为实验对象,对IdenDup的效果进行了实验探究.实验结果表明,IdenDup可以有效地识别上述两个场景下的重复缺陷报告,并且超过已有方法.

Root–shoot competition interactions cause diversity loss after fertilization:a field experiment in an alpine meadow on the Tibetan Plateau

Aims A decrease in species diversity after fertilization is a common phenomenon in grasslands;however,the mechanism causing it remains highly controversial.The light competition hypothesis to explain loss of diversity has received much attention.The aim of the present paper was to test this hypothesis.Methods Fertilization was used to control above-and belowground resources simultaneously,while shade was used to control aboveground resource in an alpine meadow on the Tibetan Plateau.Univariate general linear models was used to estimate the effects of fertilization and shade on above-and belowground vegetation characteristics,including photosynthetically active radiation(PAR)in the understory,aboveground biomass,belowground biomass,R:S ratio,species richness and Simpson’s diversity index.Important findings PAR was similar in the understory of shaded and fertilized plots,but only fertilization reduced species richness and diversity,suggesting that light competition alone could not explain diversity loss after fertilization.The root biomass and R:S ratio had a significant increase in shaded plots,but the richness and diversity did not change,suggesting that root competition alone also could not explain diversity loss after fertilization in this community.Our results illustrated that the root–shoot competition interactions,investigated from a functional groups perspective,should be the most reasonable explanation leading to the diversity loss due to fertilization.

Functional role of ATM in the cellular response to DNA damage

Ataxia-telangiectasia mutated(ATM)plays a key role in regulating the cellular response to ionizing radiation.The tumor-suppressor gene ATM,mutations in which cause the human genetic disease ataxia telangiecta-sia,encodes a key protein kinase that controls the cellular response to double-stranded breaks.Activation of ATM results in phosphorylation of many downstream targets that modulate numerous damage response pathways,most notably cell cycle checkpoints.Here,we highlight some of the new developments in thefield in our understanding of the mechanism of activation of ATM and its signaling pathways,explore whether DNA double-strand breaks are the sole activators of ATM and ATM-dependent signaling pathways,and address some of the prominent,unanswered questions related to ATM and its function.The scope of this article is to provide a brief overview of the recent literature on this subject and to raise questions that could be addressed in future studies.