Chiroptical properties of bioactive molecules: sensitivity to conformation and solvation

Chiroptical spectroscopies play a fundamental role in pharmaceutical analysis for the stereochemical characterisation of bioactive molecules, due to the close relationship between chirality and optical activity and the increasing evidence of stereoselectivity in the pharmacological and toxicological profiles of chiral drugs. The correlation between chiroptical properties and absolute stereochemistry, however, requires the development of accurate and reliable theoretical models. The present thesis will report the application of theoretical chiroptical spectroscopies in the field of drug analysis, with particular emphasis on the huge influence of conformational flexibility and solvation on chiroptical properties and on the main computational strategies available to describe their effects by means of electronic circular dichroism (ECD) spectroscopy and time-dependent density functional theory (TD-DFT) calculations. The combination of experimental chiroptical spectroscopies with state-of-the-art computational methods proved to be very efficient at predicting the absolute configuration of a wide range of bioactive molecules (fluorinated 2-arylpropionic acids, β-lactam derivatives, difenoconazole, fenoterol, mycoleptones, austdiol). The results obtained for the investigated systems showed that great care must be taken in describing the molecular system in the most accurate fashion, since chiroptical properties are very sensitive to small electronic and conformational perturbations. In the future, the improvement of theoretical models and methods, such as ab initio molecular dynamics, will benefit pharmaceutical analysis in the investigation of non-trivial effects on the chiroptical properties of solvated systems and in the characterisation of the stereochemistry of complex chiral drugs.

How to explain: from theory to practice

Today we live in an age where the internet and artificial intelligence allow us to search for information through impressive amounts of data, opening up revolutionary new ways to make sense of reality and understand our world. However, it is still an area of improvement to exploit the full potential of large amounts of explainable information by distilling it automatically in an intuitive and user-centred explanation. For instance, different people (or artificial agents) may search for and request different types of information in a different order, so it is unlikely that a short explanation can suffice for all needs in the most generic case. Moreover, dumping a large portion of explainable information in a one-size-fits-all representation may also be sub-optimal, as the needed information may be scarce and dispersed across hundreds of pages. The aim of this work is to investigate how to automatically generate (user-centred) explanations from heterogeneous and large collections of data, with a focus on the concept of explanation in a broad sense, as a critical artefact for intelligence, regardless of whether it is human or robotic. Our approach builds on and extends Achinstein’s philosophical theory of explanations, where explaining is an illocutionary (i.e., broad but relevant) act of usefully answering questions. Specifically, we provide the theoretical foundations of Explanatory Artificial Intelligence (YAI), formally defining a user-centred explanatory tool and the space of all possible explanations, or explanatory space, generated by it. We present empirical results in support of our theory, showcasing the implementation of YAI tools and strategies for assessing explainability. To justify and evaluate the proposed theories and models, we considered case studies at the intersection of artificial intelligence and law, particularly European legislation. Our tools helped produce better explanations of software documentation and legal texts for humans and complex regulations for reinforcement learning agents.