Improving (Q)SAR predictions by examining bias in the selection of compounds for experimental testing

ABSTRACT

Existing data on structures and biological activities are limited and distributed unevenly across distinct molecular targets and chemical compounds. The question arises if these data represent an unbiased sample of the general population of chemical-biological interactions. To answer this question, we analyzed ChEMBL data for 87,583 molecules tested against 919 protein targets using supervised and unsupervised approaches. Hierarchical clustering of the Murcko frameworks generated using Chemistry Development Toolkit showed that the available data form a big diffuse cloud without apparent structure. In contrast hereto, PASS-based classifiers allowed prediction whether the compound had been tested against the particular molecular target, despite whether it was active or not. Thus, one may conclude that the selection of chemical compounds for testing against specific targets is biased, probably due to the influence of prior knowledge. We assessed the possibility to improve (Q)SAR predictions using this fact: PASS prediction of the interaction with the particular target for compounds predicted as tested against the target has significantly higher accuracy than for those predicted as untested (average ROC AUC are about 0.87 and 0.75, respectively). Thus, considering the existing bias in the data of the training set may increase the performance of virtual screening.     

一种液晶环氧树脂固化中扩散控制动力学研究

根据扩散控制反应的基本原理 ,建立了合适的反应模型 ,描述了 4 ,4′ 二 ( 2 ,3 环氧丙氧基 )偶氮苯(DGEAP) / 4,4′ 二氨基二苯甲烷 (DDM)环氧树脂的固化行为 .该模型认为 ,随着环氧基团反应程度的提高 ,基团的反应半径将受到影响 .当体系中出现了介晶基元的有序排列时 ,与之相连的反应基团的分布也受到影响 ,有序区内的局部浓度将变大 ,产生假浓度效应 ,并最终影响扩散控制反应动力学 .通过与普通环氧树脂固化动力学的比较 ,证实了这一效应 .     

Temperature Dependent Dielectric Relaxation in Solvent Mixtures at Microwave Frequencies

By the use of time domain reflectometry method, dielectric measurements were carried out on dimethylformamide‐2‐nitrotoluene solvent mixtures in the frequency range 10 MHz‐20 GHz, at various temperatures from 15 °C to 45 °C. These solvent mixtures as well as pure solvents display a Debye type dispersion. Their frequency dependent dielectric properties can be summarized by the three parameters in the Debye equation: a static permittivity, permittivity at high frequency and a dielectric relaxation time constant. The free energy of activation for dipolar relaxation process and the Kirkwood correlation factor were determined using these fitting parameters for these solvent mixtures at various concentrations and temperatures. By using these dielectric parameters, the excess permittivity and excess inverse relaxation time is obtained. The excess permittivity is found to be positive for all concentrations and temperatures whereas the excess inverse relaxation time is negative.     

Analysis of post-translational modification and characterization of the domain structure of dynamin A from Dictyostelium discoideum

The post-translational modifications of the 96 kDa protein dynamin A from Dictyostelium discoideum were analyzed using Q-TOF mass spectrometry. The accurate molecular mass of the intact protein revealed a covalent modification causing an additional mass of 42 Da. The modification could be identified as N-terminal acetylation by tandem mass spectrometry. Extracted ion chromatograms for the a(1) and b(1) ion of the tryptic T1 peptide were used to detect the acetylated peptide within 54 nanoelectrospray ionization tandem mass spectra. Owing to the accurate molecular mass of the intact protein, additional covalent modifications could be excluded. In addition to the covalent modification, the domain structure of dynamin A was determined by applying a combination of limited proteolysis, sodium dodecylsulfate polyacrylamide gel electrophoresis, automated tandem mass spectrometry and protein database searching.     

The domain of partial attraction of a Poisson law

Groshev gave a characterization of the union of domains of partial attraction of all Poisson laws in 1941. His classical condition is expressed by the underlying distribution function and disguises the role of the mean of the attracting distribution. In the present paper we start out from results of the recent probabilistic approach and derive characterizations for any fixed >0 in terms of the underlying quantile function. The approach identifies the portion of the sample that contributes the limiting Poisson behavior of the sum, delineates the effect of extreme values, and leads to necessary and sufficient conditions all involving . It turns out that the limiting Poisson distributions arise in two qualitatively different ways depending upon whether >1 or <1. A concrete construction, illustrating all the results, also shows that in the boundary case when =1 both possibilities may occur.     

A characterization of brownian motion in a lipschitz domain by its killing distributions

Let (Y _t, Q^x) be a strong Markov process in a bounded Lipschitz domainD with continuous paths up to its lifetime , and let (X _t, P^x) be a Brownian motion inD. IfY _– exists in D andQ ^x(Y_– C)=P^x(X_– C) for all Borel subsetsC of D and allx, thenY is a time change ofX.     

Imaging Magnetic Domain Structures with Soft X-Ray Microscopy

The current achievements in magnetic transmission soft X-ray microscopy will be reviewed. The magnetic contrast is given by X-ray magnetic circular dichroism (X-MCD), i.e., the dependence of the absorption coefficient of circularly polarized X rays on the projection of the magnetization in a ferromagnetic system onto the photon propagation direction. X-MCD contrast can reach, e.g., at L_2,3 edges in transition metals, large values up to 50%. Combined with a soft X-ray microscope where Fresnel zone plates acting as optical elements provide a lateral resolution down at 25 nm, it allows for imaging magnetic microstructures. Specific features of this photon-based technique are the recording of images in varying external magnetic fields, an inherent chemical specificity, a high sensitivity to thin magnetic layers, due to the large contrast, and the possibility to distinguish between in-plane and out-of plane contributions. In this report, recent results obtained with the XM-1 microscope at the ALS (Berkeley/CA) demonstrate the broad applicability of this novel experimental technique to both fundamental and technological relevant issues in nanomagnetism. The future potential will be briefly outlined.     

多个时间常数线性体系暂态响应方程参数的代数求解法

从线性条件出发,推导了含n个时间常数体系恒电位阶跃时暂态响应方程,并提出一套解析形为ΔI=ΔI_∞+sum from i=1 to n k_iexp(-t/τ_i)暂态方程各未知参数的代数解法。该方法可对未知体系时间常数个数进行判定,比起一般曲线拟合更加快速简便,且抗干扰能力较强。     

脉冲泄流时土壤条件对冲击接地阻抗的影响

 为了探寻电流脉冲泄流时，设备的接地是否有效可靠，用FDTD法分析了脉冲泄流时均一土壤、分层土壤及局部改善土壤的电导率对冲击接地阻抗（TGR）的影响。结果表明：大地电导率对冲击接地阻抗的影响很大；对均一土壤，TGR随大地电导率的增大而减小，大地电导率越大，TGR对接地体的埋深越不敏感。对分层土壤，接地体要埋在大地电导率大的土壤层中，且不要靠近交界面；局部改善大地导电性能对降低TGR效果明显，TGR对改善区域的体积非常敏感，而当电导率大于一定值时，大地电导率的再增加，对TGR的影响不明显。