Predicting Skin Permeability by means of Computational Approaches : Reliability and Caveats in Pharmaceutical Studies

© 2019 American Chemical Society.The skin is the main barrier between the internal body environment and the external one. The characteristics of this barrier and its properties are able to modify and affect drug delivery and chemical toxicity parameters. Therefore, it is not surprising that permeability of many different compounds has been measured through several in vitro and in vivo techniques. Moreover, many different in silico approaches have been used to identify the correlation between the structure of the permeants and their permeability, to reproduce the skin behavior, and to predict the ability of specific chemicals to permeate this barrier. A significant number of issues, like interlaboratory variability, experimental conditions, data set building rationales, and skin site of origin and hydration, still prevent us from obtaining a definitive predictive skin permeability model. This review wants to show the main advances and the principal approaches in computational methods used to predict this property, to enlighten the main issues that have arisen, and to address the challenges to develop in future research.Peer reviewedFinal Accepted Versio

Neural Network Potential Simulations of Copper Supported on Zinc Oxide Surfaces

Heterogeneous catalysis is an area of active research, because many industrially relevant reactions involve gaseous reactants and are accelerated by solid phase catalysts. In recent years, activity in the field has become more intense due to the development of surface science and simulation techniques that allow for acquiring deeper insight into these catalysts, with the goal of producing more active, cheaper and less toxic catalytic materials. One particularly crucial case study for heterogeneous catalysis is the synthesis of methanol from synthesis gas, composed of H2, CO and CO2. The reaction is catalyzed by a mixture of Cu and ZnO nanoparticles with Al2O3 as a support material. This process is important not only due to methanol’s many uses as a solvent, raw material for organic synthesis, and possible energy and carbon capture material, but also as an example for many other metal/metal oxide catalysts. A plethora of experimental studies are available for this catalyst, as well as for simpler model systems of Cu clusters supported on ZnO surfaces. Unfortunately, there is still a lack of theoretical studies that can support these experi- mental results by providing an atom-by-atom representation of the system. This scarcity of atomic level simulations is due to the absence of fast but ab-initio level accurate potentials that would allow for reaching larger systems and longer simulated time scales. A promising possibility to bridge this gap in potentials is the rise of machine learning potentials, which utilize the tools of machine learning to reproduce the potential energy surface of a system under study, as sampled by an expensive electronic structure reference method of choice. One early and fruitful example of such machine learning force fields are neural network potentials, as initially developed by Behler and Parrinello. In this thesis, a neural network potential of the Behler-Parrinello type has been constructed for ternary Cu/Zn/O systems, focusing on supported Cu clusters on the ZnO(10-10) surface, as a model for the industrial catalyst. This potential was subsequently utilized to perform a number of simulations. Small supported Cu clusters between 4 and 10 atoms were optimized with a genetic algorithm, and a number of structural trends observed. These clusters revealed the first hints of the structure of the Cu/ZnO interface, where Cu prefers to interact with the support through configurations in the continuum between Cu(110) and Cu(111). Simulated annealing runs for Cu clusters between 200 and 500 atoms reinforced this observation, with these larger clusters also adopting this sort of interface with the support. Additionally, in these simulations the effect of strain induced by the support can be observed, with deviations from ideal lattice constants reaching the top of all of the clusters. To further investigate the influence of strain in this system, large coincident surfaces of Cu were deposited on ZnO supports. Due to the lattice mismatch present between the two materials, this requires straining the Cu overlayer. This analysis confirmed once again that Cu(110) and Cu(111) are the most stable surfaces when de- posited on ZnO(10-10). During this thesis a number of new algorithm and programs were developed. Of particular interest is the bin and hash algorithm, which was designed to aid in the construction and curating of reference sets for the neural network potential, and can also be used to evaluate the quality of atomic descriptor sets.2021-10-0

Effect of cooking time on physical properties of almond milk-based lemak cili api gravy

One of the crucial elements in developing or reformulating product is to maintain the quality throughout its entire shelf life. This study aims to determine the effect of different cooking time on the almond milk-based of lemak cili api gravy. Various cooking times of 5, 10, 15, 20, 25 and 30 minutes were employed to the almond milk-based lemak cili api gravy followed by determination of their effects on physical properties such as total soluble solids content, pH and colour. pH was determined by using a pH meter. Refractometer was used to evaluate the total soluble solids content of almond milk-based lemak cili api gravy. The colours were determined by using spectrophotometer which expressed as L*, a* and b* values. Results showed that almond milk-based lemak cili api gravy has constant values of total soluble solids with pH range of 5 to 6, which can be classified as low acid food. Colour analysis showed that the lightness (L*) and yellowness (b*) are significantly increased while redness (a*) decreased. In conclusion, this study shows that physical properties of almond milk-based lemak cili api gravy changes by increasing the cooking time

Studies on the relationships between oligonucleotide probe properties and hybridization signal intensities

Microarray technology is a commonly used tool in biomedical research for assessing global gene expression, surveying DNA sequence variations, and studying alternative gene splicing. Given the wide range of applications of this technology, comprehensive understanding of its underlying mechanisms is of importance. The focus of this work is on contributions from microarray probe properties (probe secondary structure: ?Gss, probe-target binding energy: ?G, probe-target mismatch) to the signal intensity. The benefits of incorporating or ignoring these properties to the process of microarray probe design and selection, as well as to microarray data preprocessing and analysis, are reported. Four related studies are described in this thesis. In the first, probe secondary structure was found to account for up to 3% of all variation on Affymetrix microarrays. In the second, a dinucleotide affinity model was developed and found to enhance the detection of differentially expressed genes when implemented as a background correction procedure in GeneChip preprocessing algorithms. This model is consistent with physical models of binding affinity of the probe target pair, which depends on the nearest-neighbor stacking interactions in addition to base-pairing. In the remaining studies, the importance of incorporating biophysical factors in both the design and the analysis of microarrays ‘percent bound’, predicted by equilibrium models of hybridization, is a useful factor in predicting and assessing the behavior of long oligonucleotide probes. However, a universal probe-property-independent three-parameter Langmuir model has also been tested, and this simple model has been shown to be as, or more, effective as complex, computationally expensive models developed for microarray target concentration estimation. The simple, platform-independent model can equal or even outperform models that explicitly incorporate probe properties, such as the model incorporating probe percent bound developed in Chapter Three. This suggests that with a “spiked-in” concentration series targeting as few as 5-10 genes, reliable estimation of target concentration can be achieved for the entire microarray

Quantitative Structure-Property Relationship Modeling & Computer-Aided Molecular Design: Improvements & Applications

The objective of this work was to develop an integrated capability to design molecules with desired properties. An automated robust genetic algorithm (GA) module has been developed to facilitate the rapid design of new molecules. The generated molecules were scored for the relevant thermophysical properties using non-linear quantitative structure-property relationship (QSPR) models. The descriptor reduction and model development for the QSPR models were implemented using evolutionary algorithms (EA) and artificial neural networks (ANNs). QSPR models for octanol-water partition coefficients (Kow), melting points (MP), normal boiling points (NBP), Gibbs energy of formation, universal quasi-chemical (UNIQUAC) model parameters, and infinite-dilution activity coefficients of cyclohexane and benzene in various organic solvents were developed in this work. To validate the current design methodology, new chemical penetration enhancers (CPEs) for transdermal insulin delivery and new solvents for extractive distillation of the cyclohexane + benzene system were designed. In general, the use of non-linear QSPR models developed in this work provided predictions better than or as good as existing literature models. In particular, the current models for NBP, Gibbs energy of formation, UNIQUAC model parameters, and infinite-dilution activity coefficients have lower errors on external test sets than the literature models. The current models for MP and Kow are comparable with the best models in the literature. The GA-based design framework implemented in this work successfully identified new CPEs for transdermal delivery of insulin, with permeability values comparable to the best CPEs in the literature. Also, new solvents for extractive distillation of cyclohexane/benzene with selectivities two to four times that of the existing solvents were identified. These two case studies validate the ability of the current design framework to identify new molecules with desired target properties.Chemical Engineerin

Analysed potential of big data and supervised machine learning techniques in effectively forecasting travel times from fused data

Travel time forecasting is an interesting topic for many ITS services. Increased availability of data collection sensors increases the availability of the predictor variables but also highlights the high processing issues related to this big data availability. In this paper we aimed to analyse the potential of big data and supervised machine learning techniques in effectively forecasting travel times. For this purpose we used fused data from three data sources (Global Positioning System vehicles tracks, road network infrastructure data and meteorological data) and four machine learning techniques (k-nearest neighbours, support vector machines, boosting trees and random forest). To evaluate the forecasting results we compared them in-between different road classes in the context of absolute values, measured in minutes, and the mean squared percentage error. For the road classes with the high average speed and long road segments, machine learning techniques forecasted travel times with small relative error, while for the road classes with the small average speeds and segment lengths this was a more demanding task. All three data sources were proven itself to have a high impact on the travel time forecast accuracy and the best results (taking into account all road classes) were achieved for the k-nearest neighbours and random forest techniques.</p