Musings on ADME predictions and molecular structure

In this overview, we first examine Structure-Activity Relations (SARs) and their components from a general point of view. Four types of interpretation emerging from statistically valid relations are considered, namely causal (mechanistic), contextual (empirical), fortuitous and tautological correlations. Implications for ADME predictions arise when discussing the diversity of interactions between active compounds (e.g. drugs) and biological systems. In a second part, we share our views on the differences between pharmacodynamic targets (namely the sites of action of bioactive compounds, e.g. receptors and ion channels) and pharmacokinetic agents (namely the biological components that act on drugs to transport, metabolize, retain and excrete xenobiotics). While the former are usually characterized by a high (i.e., narrow) specificity towards their ligands, the latter have evolved to recognize chemically diverse compounds and thus to display a low (i.e., broad) specificity. In a last part, we discuss the concept of molecular structure and focus on the fluctuations undergone by molecular form and functions. As a result, a molecule can exist in a large number of distinct microstates, the ensemble of which constitutes the property space of the molecule