Quantitative weight of evidence method for combining predictions of quantitative structure-activity relationship models

ABSTRACT

A method for combining statistical-based QSAR predictions of two or more binary classification models is presented. It was assumed that all models were independent. This facilitated the combination of positive and negative predictions using a quantitative weight of evidence (qWoE) procedure based on Bayesian statistics and the additivity of the logarithms of the likelihood ratios. Previous studies combined more than one prediction but used arbitrary strengths for positive and negative predictions. In our approach, the combined models were validated by determining the sensitivity and specificity values, which are performance metrics that are a point of departure for obtaining values that measure the weight of evidence of positive and negative predictions. The developed method was experimentally applied in the prediction of Ames mutagenicity. The method achieved a similar accuracy to that of the experimental Ames test for this endpoint when the overall prediction was determined using a combination of the individual predictions of more than one model. Calculating the qWoE value would reduce the requirement for expert knowledge and decrease the subjectivity of the prediction. This method could be applied to other endpoints such as developmental toxicity and skin sensitisation with binary classification models.     

A pseudoreceptor docking study of 4,5-α-epoxymorphinans with a range of dielectric constants

Summary Thirteen 4,5-epoxymorphinan agonists with established analgesic action were docked into an Asp-Lys-His-Phe pseudoreceptor complex under a range of distance-dependent dielectric conditions. The number of compounds with potential energies of the docked complexes that agreed in rank order with corresponding analgesic potencies was determined for each condition. Two dielectric conditions, n-decane (1.991) and ethanol (24.3), enabled the greatest number of compounds to relate to their pseudoreceptors with each having 9 and 8 successes respectively. Both of these conditions demonstrated unique influences on the types of structures that were successfully docked. For example, the morphine stereoisomer -isomorphine, the geometric isomer B/C trans-morphine, and the 8-position-substituted -isomorphine were successes in the n-decane condition, whereas the ethanol condition produced the substituted codeine derivatives dihydroco-deinone and dihydroxycodeinone. These findings emphasize the importance of dielectric influence when developing force-field modeled quantitative structure-activity relationships for a closely related homologous series.     

Quantitation of diethylene glycol monoethyl ether in citrus oils

The use of diethylene glycol monoethyl ether as a flavor solvent is restricted. Since existing methods of quantitation are tedious or require sophisticated multi-dimensional GC instrumentation, a simple method has been developed using low cost GC-MS. Monitoring of ions 31 and 45 enables quantitation of DEGEE in essential oils at levels down to 1 μg/g with accuracy equal to or better than 15%.     

The performance and application of a multidimensional system for gas chromatography

We have previously described [1] the design of a simple heart-cuttings device based on the Deans' principle of remote pressure switching [2]. Since that time, further work has been conducted to refine the design of the heart-cutting device and to develop complementary backflushing and cryofocusing units. This paper describes the results obtained from an intensive evaluation of the three modules in various combinations and considers parameters critical to the practical application of multidimensional gas chromatography (MDGC).     

Protease sensors for bioimaging

Optical imaging of specific molecular targets and pathways in vivo has recently become possible through continued developments in imaging equipment, reconstruction algorithms, and more importantly the availability of imaging reporter molecules. These reporter molecules encompass photoproteins expressed in vivo and exogenously administered probes detectable by fluorescence and/or bioluminescence imaging. One particularly enticing aspect of optical imaging is the ability to design activatible probes with inherent amplification. This review summarizes our experience in developing novel near-infrared fluorescent (NIRF) imaging agents that report on protease activities. These agents are designed to be biocompatible, highly activatible, and able to produce bright NIRF following protease cleavage.     

Unraveling the mystery of efficacy in Chinese medicine formula: New approaches and technologies for research on pharmacodynamic substances

Traditional Chinese medicine (TCM) is the key to unlock treasures of Chinese civilization. TCM and its compound play a beneficial role in medical activities to cure diseases, especially in major public health events such as novel coronavirus epidemics across the globe. The chemical composition in Chinese medicine formula is complex and diverse, but their effective substances resemble “mystery boxes”. Revealing their active ingredients and their mechanisms of action has become focal point and difficulty of research for herbalists. Although the existing research methods are numerous and constantly updated iteratively, there is remain a lack of prospective reviews. Hence, this paper provides a comprehensive account of existing new approaches and technologies based on previous studies with an in vitro to in vivo perspective. In addition, the bottlenecks of studies on Chinese medicine formula effective substances are also revealed. Especially, we look ahead to new perspectives, technologies and applications for its future development. This work reviews based on new perspectives to open horizons for the future research. Consequently, herbal compounding pharmaceutical substances study should carry on the essence of TCM while pursuing innovations in the field.     

Simple and rapid quantitative determination of lysinoalanine and protein hydrolysate amino acids by high-performance liquid chromatography after derivatization with dansyl chloride

Summary A rapid and simple method for the determination of both lysinoalanine (LAL) and protein hydrolysate amino acids after derivatization with dansyl chloride (5-dimethylaminoaphtalene-1sulfonyl chloride) and separation with RP-HPLC (UV detection) is presented. LAL is analysed in less than 15 minutes and complete separation of 22 amino acids is achieved in less than 30 minutes using single linear gradients of solvents (phosphate buffer and acetonitrile). Quantitative results obtained by HPLC compare well with results of the ion-exchange chromatography (amino acid analyser). The importance of the duration of the derivatization reaction and of the excess of reagent is discussed. As examples, the results of the determination of LAL in two samples of base treated α-casein and 22 samples of soy protein and the results of the analysis of amino acids in two balanced diet mixtures are presented. Presented at the 15th International Symposium on Chromatography, Nürnberg, October 1984     

Stimultaneous quantitative analysis using dual capillary columns of different polarities

Complex organic mixtures, such as coal liquefaction and oil shale products and by-products, are comprised of hundreds or thousands of individual components. State-of-the-art high resolution gas chromatography does not always provide sufficient resolution to allow accurate quantitation or identification of many compounds of interest. The concept of dual capillary column chromatography combines the different resolving characteristics of two capillary columns coated with different stationary phases into a single chromatographic run. In this approach, both columns are connected to the same injection port. Analysis of complex mixtures in this fashion can confirm the identification and quantitation of components on two columns of different polarity with little increased analysis time, can provide a means of obtaining quantitative data for individual components which are known to coelute on any one column, and can alert one to unknown coelution problems that would be undetected by gas chromatographic analysis on a single capillary column. Simultaneous dual column analysis was applied to three samples, the neutral polycyclic aromatic hydrocarbon (PAH) fraction of a Solvent Refined Coal-II (SRC-II) heavy distillate, the nitrogen-containing polycyclic aromatic compound (N-PAC) fraction of an SRC-II heavy distillate, and the basic fraction from a shale oil process water. Fused silica capillary columns coated with SE-54 and Durawax 3 were used for the analyses of the heavy distillate, while SE-54 an Carbowax 20M capillary columns were used for the analysis of the process water.     

Micellar Liquid Chromatography Study of Quantitative Retention–Activity Relationships for Antihypertensive Drugs

Use of micellar mobile phases in reversed-phase liquid chromatography (RPLC) results in hydrophobic and electrostatic sites for interaction. Modified stationary phases in micellar liquid chromatography (MLC) are structurally similar to biomembranes. To confirm this we focused on the effects of the type and concentration of surfactant (Brij 35, SDS, and CTAB) and mobile phase pH on the retention of antihypertensive drugs on modified C₁₈ stationary phases. Quantitative retention-activity relationships are proposed for the drugs and the different surfactants and compared with those obtained using aqueous–organic mobile phases. Finally, a correlation was obtained between the logarithm of retention factors (log k) and the toxicity (LD₅₀) of antihypertensive drugs. Revised: 14 September 2005 and 4 April 2006     

From a point-like to an arbitrarily shaped sample: A survey of equations for electron paramagnetic resonance signal intensity calculations

A set of original, analytical equations useful for theoretical calculation of the electron paramagnetic resonance (EPR) signal intensity are presented for the multitude of sample shapes, which range from point-like, line-like, planar, rectangular, cubical, circular, cylindrical, spherical to an irregularly shaped sample. The samples can be situated at any available position within the prescribed part of the microwave cavity (a central cylinder of diameter 11 mm and length 23.5 mm, in either a Bruker single TE₁₀₂ or double TE₁₀₄ rectangular cavity, with the modulation coils situated in the left and right side cavity walls, which is connected to a X-band, field-modulated CW Bruker EPR spectrometer). The theoretical computations of EPR signal intensity can be used in the computer simulations in which: (i) the EPR signal intensity profiles are constructed; (ii) the optimal sample positions in the cavity to give a maximum value of signal intensity are found; (iii) the errors associated with sample positioning within the cavity when compared to a second sample of a different size, shape or position are studied.