Three-dimensional quantitative structure activity relationships of quorum-sensing and biofilm inhibitors in gram-negative bacteria

Thirty N-acyl homoserine lactone (AHL) analogs with variable antibacterial activity and displaying inhibition of biofilm formation were selected to develop models for establishing three-dimensional quantitative structure-activity relationships (3D-QSAR). Comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) were carried out to determine the optimum structural requirements for selectivity and potency of quorum-sensing and bacterial biofilm inhibition. The best CoMFA model predicted a q² value of 0.519 and an r² value of 0.984 and revealed that electrostatic and steric properties play a significant role in potency and selectivity. The CoMSIA model predicted a q² value of 0.411 and an r² value of 0.938 based on a combination of steric, electrostatic, and hydrophobic effects. The analysis of the contour maps from each model provide insight into the structural requirements for increasing the activity of a compound. Consequently, manipulating the chemical and physical properties of substituted acyl groups on the homoserine lactone moiety can provide important information toward enhancing the antibacterial properties of the target chemical compound.     

Occurrence and ecological hazard assessment of selected veterinary medicines in livestock wastewater treatment plants

The occurrence of some veterinary medicines in the livestock wastewater plants (WWTPs) was investigated. This investigation represented the occurrence of veterinary medicines to treat in the livestock WWTPs or be discharged into the water system in Korea since the sampling sites were widely distributed across the nation and samples were collected from the 11 livestock WWTPs. Nine antibiotics, two analgesics, and two disinfectants occurred in the livestock wastewater plants (WWTPs). From 11 livestock WWTP influents, chlortetracycline, oxytetracycline, acetylsalicylic acid, and disinfectants frequently occurred with the high concentrations. Meanwhile, sulfamethoxazole, erythromycin-H₂O, and trimethoprim did not occur during sampling periods. The values for log Kow of each chemical showed a high correlation with the number of hydrogen bonding acceptors and were important parameters to estimate and understand the biodegradability and toxicity of a compound in the environment. The biodegradability of each compound was proportional to the hydrophilicity of each compound and the toxicity was proportional to the number of hydrogen bonding acceptors of each compound. The expected introductory concentration (EIC), predicted exposure concentration (PEC), and hazard quotient showed that the livestock WWTP effluents were hazardous to ecosystems.     

Optimal descriptor as a translator of eclectic information into the prediction of membrane damage by means of various TiO2 nanoparticles

The increasing use of nanomaterials incorporated into consumer products leads to the need for developing approaches to establish “quantitative structure–activity relationships” (QSARs) for various nanomaterials. However, the molecular structure as rule is not available for nanomaterials at least in its classic meaning. An possible alternative of classic QSAR (based on the molecular structure) is the using of data on physicochemical features of TiO₂ nanoparticles. The damage to cellular membranes (units L⁻¹) by means of various TiO₂ nanoparticles is examined as the endpoint.     

Integrated testing and intelligent assessment—new challenges under REACH

BACKGROUND, AIM AND SCOPE: Due to a number of drawbacks associated with the previous regime for the assessment of new and existing chemicals, the European Union established a new regulation concerning the registration, evaluation, authorisation and restriction of chemicals (REACH). All relevant industrial chemicals must now be assessed. Instead of the authorities, industry itself is responsible for the risk assessment. To achieve better and more efficient assessments while reducing animal testing, all information-standard, non-standard and non-testing-has to be used in an integrated manner. To meet these challenges, the current technical guidance documents for risk assessment of new and existing chemicals had to be updated and extended considerably. This was done by experts in a number of REACH Implementation Projects. This paper presents the most relevant results of the expert Endpoint Working Group on Aquatic Toxicity in order to illustrate the change of paradigm in the future assessment of hazards to the aquatic environment by chemical substances. MAIN FEATURES AND CHALLENGES: REACH sets certain minimum data requirements in order to achieve a high level of protection for human health and the environment. It encourages the assessor to use alternative information instead of or in addition to standard one. This information has to be equivalent to the standard information requirement and adequate to draw overall conclusions with respect to the regulatory endpoints classification and labelling, persistent, bioaccumulative and toxic (PBT) assessment and predicted no-effect concentrations (PNEC) derivation. The main task of the expert working group was to develop guidance on how to evaluate the toxicity of a substance based on integration of information from different sources and of various degrees of uncertainty in a weight of evidence approach. INTEGRATED TESTING AND INTELLIGENT ASSESSMENT: In order to verify the equivalence and adequacy of different types of information, a flexible sequence of steps was proposed, covering characterisation of the substance, analysis of modes of action, identification of possible analogues, evaluation of existing in vivo and in vitro testing data as well as of QSAR results. Finally, all available data from the different steps have to be integrated to come to an overall conclusion on the toxicity of the substance. This weight of evidence approach is the basis for the development of integrated testing strategies (ITS), in that the available evidence can help to determine subsequent testing steps and is essential for an optimal assessment. Its flexibility helps to meet the different requirements for drawing conclusions on the endpoints classification and labelling, PNEC derivation as well as PBT assessment. The integration of all kinds of additional information in a multi-criteria assessment reduces the uncertainties involved with extrapolation to the ecosystem level. The weight of evidence approach is illustrated by practical examples. CONCLUSIONS AND PERSPECTIVES: REACH leads to higher challenges in order to make sound decisions with fewer resources, i.e. to move away from extensive standard testing to an intelligent substance-tailored approach. Expert judgement and integrated thinking are key elements of the weight of evidence concept and ITS, potentially leading to better risk assessments. Important sub-lethal effects such as endocrine disruption, which are not covered by the current procedure, can be considered. Conclusions have to be fully substantiated: Risk communication will be an important aspect of future assessments.     

连接性指数对脂肪醇的QSPR/QSAR研究

用碳原子取代醇中的氧,构造出极性很小、结构和原化合物相似的分子.定义原子特征值f_i=1 sum h_(ij),并在邻接矩阵的基础上,建立该化合物的连接性指数~mG,~mG=sum(f_i·f_i·f_k…)~0.5,其中,~0C=sum(f_i)~0.5.G=sum(f_i·f_i)~0.5.~mG对脂肪醇异构体具有很强的区分能力,且~0G与醇的-lgS_w,lgK_ow均有良好的相关性,复相关系数均在0.99以上.~0G具有物理意义明确,计算简单等优点.     

A simple dermal absorption model: Derivation and application

This paper deals with the derivation of a QSAR for the estimation of:

• the skin permeation coefficient from aqueous solutions in cm h⁻¹,

• the stratum corneum/water partition coefficient.

These QSARs enable the estimation of:

• the aqueous permeation coefficient in cm h⁻¹,

• the maximum dermal absorption in mg cm⁻² h⁻¹ from a saturated aqueous solution at steady state,

• the lag time in hours (h),

• the diffusivity of a substance in the stratum corneum in cm² h⁻¹

By using the independent variables:

• the log(octanol/water partition coefficient),

• the molecular weight,

• the water solubility.

The estimated maximum dermal absorption and the lag time were compared with some recent measured data of substances, which were not used for developing the QSARs. The estimates were generally in the same order of magnitude as the measured absorption and lag time. These QSARs are recommended for risk assessment of chemicals in the scope of the European REACH legislation.     

烃基酚类化合物结构与毒性关系研究

有机化合物通常由电性各异的氢、碳、氮、氧、硫及卤素等原子以共价键结合而成,从分子的三维空间结构出发,按照不同类型原子之间电性相互作用得到一种分子结构表达方法--三维分子电性相互作用矢量(three dimensional molecular electronegativity interaction vector,3D...     

咪唑类离子液体毒性的QSAR/QSPR研究

离子液体因其独特的物化性质广受关注,被誉为"新一代绿色溶剂".用定量结构-性质/活性相关(QSAR/QSPR)方法建立了43种咪唑类离子液体毒性的多元线性回归预测模型,并用10种物质进行了外部测试.模型中包含了启发式算法筛选出的6个结构描述符,其统计数据分别为R2=0.921,R2CV=0.894,F=70.35,S2=0.098,外部测试集的R2=0.952.结果表明,该模型具有良好的可靠性,可用于咪唑类离子液体的毒性预测.     

基于QSAR模型预测有机污染物在XAD与空气中的分配系数

基于定量构效关系(QSAR),运用线性(逐步多元回归MLR)和非线性(支持向量机SVM)两种计算方法开发了两种可靠且高效预测聚苯乙烯二乙烯基苯树脂(XAD)和空气之间分配系数(K_XAD-A)的模型.构建模型的数据包含醇类(Alcohols),苯类(Benzenes),多氯联苯(PCBs)和多环芳香烃(PAHs)等,共计70种有机污染物.两个模型的决定系数R²_adj和外部验证系数Q²_ext均在0.930以上,同时所有物质均在定义的应用域内,结果表明两种QSAR模型有较高的拟合度、稳健性和较为优秀的预测能力,且非线性(SVM)模型比线性(MLR)模型的拟合效果更好.