Ligand Recognition and Specificity of Metabolic Enzymes and Nuclear Receptors

Molecular recognition is a key process in the formation of ligand-protein complexes concerning both selectivity and stability of binding. Hence, it is a fundamental principle for most biological processes in the human body. In the context of pharmaceutical chemistry, it covers ligand-protein interactions, effects of the surrounding solvent, allosteric regulation, and conformational adaptation - important effects for the design of drug molecules. The foundation for the principle of recognition was already proposed in the 19th century by Emil Fischer who formulated the lock-and-key principle, which remains significant until today although with slight adjustments. The formation of ligand-protein complexes is a dynamic event. While shallow binding sites often display comparatively simple molecular recognition, the access to buried binding pockets, as they for example occur in cytochrome P450 enzymes (CYPs) or nuclear receptors (NRs), is a complex event with high relevance for binding kinetics and specificity. The consideration of target specificity is a crucial aspect for the successful design of drugs with acceptable, or in the best case, no side effects at all. Correspondingly, binding to anti-targets is one of the most relevant reasons for economically devastating drug attrition in clinical development. Hence, the detailed understanding of molecular recognition is of pivotal importance. In this regard, computational methods provide a cost effective approach to study the underlying phenomena. This thesis addresses various aspects of ligand recognition in the framework of drug-metabolizing enzymes and nuclear receptors including ligand-protein association, allosteric modulation and communication, specificity, as well as ligand-induced conformational adaptation