Molecular Mechanism-Based Network-like Similarity Graphs Reveal Relationships between Different Types of Receptor Ligands and Structural Changes that Determine Agonistic, Inverse-Agonistic, and Antagonistic Effects

Receptor ligands might act as agonists, partial agonists, inverse agonists, or antagonists and it is often difficult to understand structural modifications that alter the mechanism of action. In order to compare ligands that are active against a given receptor but have different mechanisms of action, we have designed molecular networks that mirror similarity relationships and incorporate both mechanism of action information and mechanism-specific SAR features. These network representations make it possible to systematically evaluate relationships between different types of receptor ligands and identify communities of structurally very similar ligands with different mechanisms. From a series of such ligands, structural modifications can often be deduced that lead to "mechanism hops".