A Similarity Based Approach for Chemical Category Classification

This report aims to describe the main outcomes of an IHCP Exploratory Research Project carried out during 2005 by the European Chemicals Bureau (Computational Toxicology Action). The original aim of this project was to develop a computational method to facilitate the classification of chemicals into similarity-based chemical categories, which would be both useful for building (Q)SAR models (research application) and for defining chemical category proposals (regulatory application).JRC.I-Institute for Health and Consumer Protection (Ispra

Computer Aided Aroma Design. II. Quantitative structure-odour relationship

Computer Aided Aroma Design (CAAD) is likely to become a hot issue as the REACH EC document targets many aroma compounds to require substitution. The two crucial steps in CAMD are the generation of candidate molecules and the estimation of properties, which can be difficult when complex molecular structures like odours are sought and their odour quality are definitely subjective or their odour intensity are partly subjective as stated in Rossitier’s review (1996). The CAAD methodology and a novel molecular framework were presented in part I. Part II focuses on a classification methodology to characterize the odour quality of molecules based on Structure – Odour Relation (SOR). Using 2D and 3D molecular descriptors, Linear Discriminant Analysis (LDA) and Artificial Neural Network are compared in favour of LDA. The classification into balsamic / non balsamic quality was satisfactorily solved. The classification among five sub notes of the balsamic quality was less successful, partly due to the selection of the Aldrich’s Catalog as the reference classification. For the second case, it is shown that the sweet sub note considered in Aldrich’s Catalog is not a relevant sub note, confirming the alternative and popular classification of Jaubert et al., (1995), the field of odours

Review of Data Sources, QSARs and Integrated Testing Strategies for Skin Sensitisation

This review collects information on sources of skin sensitisation data and computational tools for the estimation of skin sensitisation potential, such as expert systems and (quantitative) structure-activity relationship (QSAR) models. The review also captures current thinking of what constitutes an integrated testing strategy (ITS) for this endpoint. The emphasis of the review is on the usefulness of the models for the regulatory assessment of chemicals, particularly for the purposes of the new European legislation for the Registration, Evaluation, Authorisation and Restriction of CHemicals (REACH), which entered into force on 1 June 2007. Since there are no specific databases for skin sensitisation currently available, a description of experimental data found in various literature sources is provided. General (global) models, models for specific chemical classes and mechanisms of action and expert systems are summarised. This review was prepared as a contribution to the EU funded Integrated Project, OSIRIS.JRC.I.3-Consumer products safety and qualit

Chemoinformatics approaches for new drugs discovery

Chemoinformatics uses computational methods and technologies to solve chemical problems. It works on molecular structures, their representations, properties and related data. The first and most important phase in this field is the translation of interconnected atomic systems into in-silico models, ensuring complete and correct chemical information transfer. In the last 20 years the chemical databases evolved from the state of molecular repositories to research tools for new drugs identification, while the modern high-throughput technologies allow for continuous chemical libraries size increase as highlighted by publicly available repository like PubChem [http://pubchem.ncbi.nlm.nih.gov/], ZINC [http://zinc.docking.org/], ChemSpider[http://www.chemspider. com/]. Chemical libraries fundamental requirements are molecular uniqueness, absence of ambiguity, chemical correctness (related to atoms, bonds, chemical orthography), standardized storage and registration formats. The aim of this work is the development of chemoinformatics tools and data for drug discovery process. The first part of the research project was focused on accessible commercial chemical space analysis; looking for molecular redundancy and in-silico models correctness in order to identify a unique and univocal molecular descriptor for chemical libraries indexing. This allows for the 0%-redundancy achievement on a 42 millions compounds library. The protocol was implemented as MMsDusty, a web based tool for molecular databases cleaning. The major protocol developed is MMsINC, a chemoinformatics platform based on a starting number of 4 millions non-redundant high-quality annotated and biomedically relevant chemical structures; the library is now being expanded up to 460 millions compounds. MMsINC is able to perform various types of queries, like substructure or similarity search and descriptors filtering. MMsINC is interfaced with PDB(Protein Data Bank)[http://www.rcsb.org/pdb/home/home.do] and related to approved drugs. The second developed protocol is called pepMMsMIMIC, a peptidomimetic screening tool based on multiconformational chemical libraries; the screening process uses pharmacophoric fingerprints similarity to identify small molecules able to geometrically and chemically mimic endogenous peptides or proteins. The last part of this project lead to the implementation of an optimized and exhaustive conformational space analysis protocol for small molecules libraries; this is crucial for high quality 3D molecular models prediction as requested in chemoinformatics applications. The torsional exploration was optimized in the range of most frequent dihedral angles seen in X-ray solved small molecules structures of CSD(Cambridge Structural Database); by appling this on a 89 millions structures library was generated a library of 2.6 x 10 exp 7 high quality conformers. Tools, protocols and platforms developed in this work allow for chemoinformatics analysis and screening on large size chemical libraries achieving high quality, correct and unique chemical data and in-silico model

Thioflavin T triggers \u3b2 amyloid peptide (1-40) fibrils formation.

Introduction A general characteristic of aggregation is the multiple interaction and cross-feedback among distinct mechanisms occurring at different hierarchical levels. The comprehension of the different species interconversion during aggregation is very important since emerging evidences indicate intermediate oligomeric aggregates as primary toxic species. In this context, A\u3b2 amyloid peptide provides a challenging model for studying aggregation phenomena both for the complexity of its association process and for the direct implications in Alzheimer\u2019s Disease. Aggregates growth conditions strongly affect the final morphology, the fibrillar molecular structure as well as the aggregation pathway which is characterized by the occurrence of multiple transient species. Methods The fluorescent dye Thioflavin T (ThT) is widely used to detect amyloid deposits and it is often used in situ to study aggregation kinetics, under the hypothesis that its presence does not affect the aggregation processes under study. Here we present an experimental study on A\u3b2(1-40) peptide fibrillation kinetics at pH 7.4. In the observed conditions, A\u3b2(1- 40) undergoes aggregation only if Thioflavin T is present in solution. This phenomenon was analyzed as a function of temperature, ThT and peptide concentrations in order to explore the underlying fibrillation mechanism. Light scattering, ThT fluorescence emission, two photon excitation fluorescence microscopy, were used in a kinetic fashion to highlight different sides and critical phases of the aggregation pathway. Circular Dichroism and FTIR measurements are used to characterize secondary structure of the aggregates. Results The selected approach gives detailed information on the time evolution of A\u3b2(1-40) fibrillation process highlighting structural changes at molecular level, different aggregate species growth and their morphologies. Our data show that A\u3b2(1-40) fibrillation process occurs only in the presence of ThT and that the observed aggregation involves at least three different aggregation mechanisms acting in competition. In the first step, small oligomers, which bind ThT, are formed via non nucleated polymerization mechanism and represent an activated state for following fibrils growth. This process appear to be a rate limiting step for two distinct fibril nucleation mechanisms probably affected by an high degree of spatial heterogeneity. Conclusions We demonstrated that in the selected experimental conditions ThT triggers the A\u3b2(1 1240) fibrillation process (D\u2019Amico et. al 2012). Sterical and chemical properties of ThT molecule may modulate the peptide conformation, with similar mechanisms to the ones that usually drive the binding of this dye to already formed amyloids. So, the presence of ThT in solution may change the thermodynamic equilibrium trapping specificmore ordered conformations prone to supramolecular assembly

Skin Sensitisation (Q)SARs/Expert Systems: from Past, Present to Future

This review describes the state of the art of available (Q)SARs/expert systems for skin sensitisation and evaluates their utility for potential regulatory use. There is a strong mechanistic understanding with respect to skin sensitisation which has facilitated the development of different models. Most existing models fall into one of two main categories either they are local in nature, usually specific to a chemical class or reaction chemical mechanism or else they are global in form, derived empirically using statistical methods. Some of the published global QSARs available have been recently characterised and evaluated elsewhere in accordance with the OECD principles. An overview of expert systems capable of predicting skin sensitisation is also provided. Recently, a new perspective regarding the development of mechanistic skin sensitisation QSARs so-called Quantitative Mechanistic Modelling (QMM) has been proposed, where reactivity and hydrophobicity, are used as the key parameters in mathematically modelling skin sensitisation. Whilst hydrophobicity can be conveniently modelled using log P, the octanol-water partition coefficient; reactivity is less readily determined from chemical structure. Initiatives are in progress to generate reactivity data for reactions relevant to skin sensitisation but more resources are required to realise a comprehensive set of reactivity data. This is a fundamental and necessary requirement for the future assessment of skin sensitisation.JRC.I.3-Toxicology and chemical substance

Diffraction and database analyses of photoactive biphenyl compounds and novel carbaborane structures

The research involved in this thesis is mainly concerned with crystallography and the analysis using crystallographic techniques and methods. The work in this thesis is centered mainly on two types of chemical compounds, photoactive compounds and carbaboranes. The first is the photoactive compounds of biphenyl, its derivatives and similar compounds; these compounds have been studied by diffraction and database analysis. The photochemistry and subsequent structural analysis of biphenyls has been studied in collaboration with Professor Peter Wan at the University of Victoria, Canada. In this study Professor Wan and his group conducted all synthesis and spectroscopic analysis, including the photochemical analysis. In a similar study although not with biphenyls, the a-azidocinnamates were investigated in collaboration with Professor Meth-Cohn of the University of Sunderland. Professor Meth-Cohn and his group conducted all synthesis and spectroscopic analysis. The biphenyl type compounds have also been studied using database analysis to examine the bond lengths, torsion angles, inter-/intra-molecular interactions and general packing conformations and interactions within these structures and this analysis was used to study several conformational anomalies that exist in biphenyl derivative compounds. The second chemical type is carbaboranes; these compounds have been examined in collaboration with Professor Wade's group at the University of Durham. The analysis of carbaboranes centers mainly on hydrogen bonding however also expands into several novel carbaborane structures. Professor Wade and his group carried out the synthesis and spectroscopic analysis

A quantum crystallographic approach to study properties of molecules in crystals

In this dissertation, the behaviour of atoms, bonds, functional groups and molecules in vacuo but especially also in the crystal is studied using quantum crystallographic methods. The goal is to deepen the understanding of the properties of these building blocks as well as of the interactions among them, because good comprehension of the microscopic units and their interplay also enables us to explain the macroscopic properties of crystals. The first part (chapters 1-3) and second part (chapter 4) of this dissertation contain theoretical introductions about quantum crystallography. On the one hand, this expression contains the termquantum referring to quantumchemistry. Therefore, the very first chapter gives a brief overview about this field. The second chapter addresses different options to partition quantum chemical entities, such as the electron density or the bonding energy, into their components. On the other hand, quantumcrystallography consists obviously of the crystallographic part and chapter 3 covers these aspects focusing predominantly on X-ray diffraction. A more detailed introduction to quantum crystallography itself is presented in the second part (chapter 4). The third part (chapters 5-9) starts with an overview of the goals of this work followed by the results organized in four chapters. The goal is to deepen the understanding of properties of crystals by theoretically analysing their building block. It is for example studied how electrons and orbitals rearrange due to the electric field in a crystal or how high pressure leads to the formation of new bonds. Ultimately, these findings shall help to rationally design materials with desired properties such as high refractive index or semiconductivity.Mithilfe quantenkristallografischer Methoden werden Atome, Bindungen, funktionellen Gruppen und Moleküle in vacuo aber vor allem auch in Kristallen untersucht. Das Ziel ist es die Eigenschaften dieser Bestandteile zu verstehen und wie sie miteinander interagieren. Das Verständnis der Verhaltensweise der einzelnen Bausteine sowie deren Zusammenspiel auf mikroskopischer Ebene kann auch die makroskopischen Eigenschaften von Kristallen erklären. Der erste Teil dieser Doktorarbeit (Kapitel 1-3) beinhaltet eine theoretische Einleitung in die verschiedenen Bereiche der Quantenkristallografie. Wie der Name Quantenkristallografie besagt, besteht diese zum einen aus dem quantenchemischen Teil, weswegen das erste Kapitel eine kurze Einführung in die Quantenchemie gibt. Das zweite Kapitel widmet sich den verschiedenen Möglichkeiten quantenchemische Grössen wie zum Beispiel die Elektronendichte oder Bindungsenergien in Einzelteile zu zerlegen. Zum anderen trägt der kristallografische Teil zur Quantenkristallografie bei. Kapitel drei besteht daher aus einem kurzen Überblick über die Kristallografie mit Fokus auf der Röntgenbeugung. Anschliessend folgt im zweiten Teil (Kapitel 4) eine ausführlichere Einleitung in die Quantenkristallografie selbst. Der dritte Teil (Kapitel 5-9) beginnt mit einer kurzen Übersicht über die Ziele dieser Arbeit worauf die Resultate, gegliedert in vier verschiedene Kapitel, folgen. Das Ziel dieser Arbeit ist es die Eigenschaften von Kristallen besser zu verstehen, indem man ihre Einzelteile theoretisch analysiert und mit verschiedenen Methoden rationalisiert. Beispielsweise wird untersucht wie sich Elektronen und Orbitale aufgrund des elektrischen Feldes in Kristallen neu anordnen oder wie unter hohem Druck Bindungen neu geformt werden. Schlussendlich können all diese Erkenntnisse helfen, Materialien mit spezifischen gewünschten Eigenschaften herzustellen.Les atomes, les liaisons entre eux, les groupes fonctionnels et les molécules sont examinés en utilisant des méthodes de la cristallographie quantique. Le but est de comprendre les propriétés de ces composants et comment ils interagissent in vacuo mais surtout aussi dans les cristaux. En comprenant leurs caractéristiques et interactions au niveau microscopique, on peut aussi rationaliser les propriétés macroscopiques des cristaux. La première partie (chapitres 1-3) de cette thèse de doctorat contient une introduction brève à la cristallographie quantique. Comme le noml’indique, ce domaine de recherche est composé de la chimie quantique et la cristallographie. Pour cette raison le premier chapitre donne une introduction à la chimie quantique. Le deuxième chapitre présente quelques méthodes de décomposition des quantités de la chimie quantique comme la densité électronique ou l’énergie de liaison. Le troisième chapitre couvre la partie cristallographique. Ensuite dans la deuxième partie (chapitre 4) une introduction plus détaillée sur la cristallographie quantique elle-même est donnée. La troisième partie (chapitres 5-9) commence par un aperçu des objectives de cette dissertation suivis des résultats structurés en quatre chapitres. Le but est de comprendre les propriétés des cristaux en analysant leurs building blocks avec différentes méthodes théoriques. Il était par example examiné comment les électrons et les orbitales se réorganisent dans un cristal à cause du champ électrique ou comment des nouvelles liaisons sont formées sous pression. Finalement on peut utiliser ces conclusions pour modeler des matériaux avec des propriétés désirées

Potential Energy Minimization as the Driving Force for Order and Disorder in Organic Layers

The topic of this work is the structural characterization and theoretical modeling of organic single and heterolayers. The growth of sub-monolayers and monolayers (ML) of the two polycyclic aromatic hydrocarbons quaterrylene (QT) and hexa-peri-hexabenzocoronene (HBC) on Ag(111) and Au(111) was investigated. A transition from a disordered, isotropic phase to an ordered phase with increasing coverage was found. The lattice of the ordered phase turned out to be coverage dependent. The intermolecular potential was modeled including Coulomb and van der Waals interaction by a force-field approach. The postulated repulsive character of the potential could be connected to the non-uniform intramolecular charge distribution and to a screening of the van der Waals forces. Furthermore, the influence of the variable lattice constant on the epitaxial growth of HBC was studied. The second part of this work deals with a ML of 3,4,9,10-perylenetetracarboxylic dianhydride (PTCDA) on a ML of HBC. In dependency on the initial lattice constant of HBC, a total of three line-on-line (LOL) and point-on-line coincident phases of PTCDA (with respect to HBC) was found. Following an analysis of the general properties of LOL coincident systems via force-field calculations, a new method to predict the structure of such systems is introduced.:1 Introduction 2 Experimental Methods 2.1 Organic molecular beam epitaxy 2.2 Scanning tunneling microscopy (STM) 2.3 Low-energy electron diffraction (LEED) 2.4 Molecules and substrates: Basic properties and literature review 2.4.1 3,4,9,10-Perylenetetracarboxylic dianhydride 2.4.2 Hexa-peri-hexabenzocoronene 2.4.3 Quaterrylene 2.4.4 Metal substrates: Au(111) and Ag(111) 3 Theory and Modeling 3.1 Reciprocal space and LEED 3.1.1 Fourier transform and geometrical LEED theory 3.1.2 Kinematic and dynamic LEED theory 3.1.3 Further applications of the Fourier transform 3.2 Computational chemistry 3.2.1 Calculating molecular properties 3.2.2 The atomic force-field method 3.2.3 Potential energy calculations in extended systems 4 Epitaxy in terms of potential energy 5 Interaction of QT and HBC at Sub-ML and ML Coverage 5.1 Experimental results 5.2 Modeling technique 5.3 Results of the model calculation 5.4 Discussion of results 5.5 Conclusion 6 The Ordered Phases of HBC on Ag(111) and Au(111 6.1 Geometrical analysis of epitaxy 6.2 Energetic gain of epitaxial structures 6.3 Comparison to experiment 6.4 Influence of the Au(111) surface reconstruction 6.5 Conclusion 7 Organic Heterosystems of PTCDA and HBC on Au(111) 7.1 PTCDA on Au(111) revisited 7.2 LEED and STM on PTCDA/HBC/Au(111) samples 7.2.1 A “compact” HBC layer substrate 7.2.2 A “loosely packed” HBC layer substrate 7.2.3 Summary of LEED results 7.2.4 STM results 7.3 Epitaxial relations in the system PTCDA/HBC/Au(111) 7.3.1 Geometrical analysis of epitaxy 7.3.2 Energetic gain of epitaxial structures 7.3.3 Mutual alignment of lattices 7.4 Heterosystems of PTCDA and HBC with inverted stacking sequence 8 General Properties of POL and LOL Epitaxy 8.1 A new coordinate system 8.2 Specific properties of the substrate-adsorbate potential 8.3 The “natural order” of the lattice lines 8.4 Prediction of epitaxial growth - a “LOL predictor” 8.4.1 Method 8.4.2 Results 9 General Conclusions and Future Perspectives 9.1 Conclusion 9.2 Outlook Appendix A.1 Conductance in a STM: The 1D WKB model A.2 Extraction of the DOS from STS measurements by means of the 1D WKB model A.3 Practical application of the 1D WKB model A.4 The normalized differential conductivity A.5 A new normalization methodThema dieser Arbeit ist die strukturelle Charakterisierung von organischen Einfach- und Heterolagen sowie deren theoretische Beschreibung und Modellierung. Es wurden Submonolagen und Monolagen (ML) der polyzyklischen Kohlenwasserstoffe Quaterrylen (QT) und Hexa-peri-hexabenzocoronen (HBC) auf Ag(111) und Au(111) Einkristallen untersucht und ein Übergang von einer ungeordneten, isotropen Phase zu einer geordneten Phase mit steigender Bedeckung beobachtet. Die geordnete Phase wies dabei bedeckungsabhängige Gitterkonstanten auf. Das intermolekulare Potential wurde unter Berücksichtigung von Coulomb und van der Waals Anteilen mittels Kraftfeldmethoden modelliert. Der postulierte repulsive Charakter des Potentials konnte auf die Ladungsverteilung im Molekül und eine Abschwächung des van der Waals Potentials zurückgeführt werden. Weiterhin wurde der Einfluss der variablen HBC Gitterkonstante auf die epitaktische Relation des Gitters zum Metallsubstrat untersucht. Der zweite Teil der Arbeit widmet sich der Untersuchung einer ML 3,4,9,10-Perylenetetracarboxylic dianhydrid (PTCDA) auf einer ML HBC. Dabei wurden, in Abhängigkeit von der HBC Gitterkonstante, insgesamt drei verschiedene Typen von line-on-line bzw. point-on-line Epitaxie nachgewiesen. Im Anschluss an eine Analyse der generellen Eigenschaften solcher epitaktischer Lagen mittels Kraftfeldrechnungen wird eine neue Methode zur Vorhersage der Struktur konkreter Systeme vorgestellt.:1 Introduction 2 Experimental Methods 2.1 Organic molecular beam epitaxy 2.2 Scanning tunneling microscopy (STM) 2.3 Low-energy electron diffraction (LEED) 2.4 Molecules and substrates: Basic properties and literature review 2.4.1 3,4,9,10-Perylenetetracarboxylic dianhydride 2.4.2 Hexa-peri-hexabenzocoronene 2.4.3 Quaterrylene 2.4.4 Metal substrates: Au(111) and Ag(111) 3 Theory and Modeling 3.1 Reciprocal space and LEED 3.1.1 Fourier transform and geometrical LEED theory 3.1.2 Kinematic and dynamic LEED theory 3.1.3 Further applications of the Fourier transform 3.2 Computational chemistry 3.2.1 Calculating molecular properties 3.2.2 The atomic force-field method 3.2.3 Potential energy calculations in extended systems 4 Epitaxy in terms of potential energy 5 Interaction of QT and HBC at Sub-ML and ML Coverage 5.1 Experimental results 5.2 Modeling technique 5.3 Results of the model calculation 5.4 Discussion of results 5.5 Conclusion 6 The Ordered Phases of HBC on Ag(111) and Au(111 6.1 Geometrical analysis of epitaxy 6.2 Energetic gain of epitaxial structures 6.3 Comparison to experiment 6.4 Influence of the Au(111) surface reconstruction 6.5 Conclusion 7 Organic Heterosystems of PTCDA and HBC on Au(111) 7.1 PTCDA on Au(111) revisited 7.2 LEED and STM on PTCDA/HBC/Au(111) samples 7.2.1 A “compact” HBC layer substrate 7.2.2 A “loosely packed” HBC layer substrate 7.2.3 Summary of LEED results 7.2.4 STM results 7.3 Epitaxial relations in the system PTCDA/HBC/Au(111) 7.3.1 Geometrical analysis of epitaxy 7.3.2 Energetic gain of epitaxial structures 7.3.3 Mutual alignment of lattices 7.4 Heterosystems of PTCDA and HBC with inverted stacking sequence 8 General Properties of POL and LOL Epitaxy 8.1 A new coordinate system 8.2 Specific properties of the substrate-adsorbate potential 8.3 The “natural order” of the lattice lines 8.4 Prediction of epitaxial growth - a “LOL predictor” 8.4.1 Method 8.4.2 Results 9 General Conclusions and Future Perspectives 9.1 Conclusion 9.2 Outlook Appendix A.1 Conductance in a STM: The 1D WKB model A.2 Extraction of the DOS from STS measurements by means of the 1D WKB model A.3 Practical application of the 1D WKB model A.4 The normalized differential conductivity A.5 A new normalization metho

New Strategies in Quantitative Structure-Activity Relationships. Applications to Adenosine Receptor Ligands

Over the last years, an increasing number of applications of QSAR (Quantitative Structure-Activity Relationships) appeared in the literature, not only in lead finding and lead optimization, but also in other fields related to drug discovery, such as ADMET predictions. Neverthless, many questions are still open and they supplied the starting point of this research. Attention was focused on characteristics usually intended as “pitfalls” of QSAR itself. In this work, each step of the QSAR model development process was handled with a rational and rigorous approach, and the classic QSAR strategies were implemented with new protocol