A simple theory to explain super-additivity of highly similar drug combinations

Small-molecule drugs canonically act by binding to a specific site on a single protein, leading to a change in the protein’s activity. In particular, allosteric agonists bind preferentially to the active form of the protein, increasing the population of the active state and increasing activity. Hence, it is not surprising that similar compounds often act in similar ways, because they naturally bind to the same sites. However, recent work has provided examples of closely related small molecules that act super-additively when co-administered, a phenomenon that is difficult to explain using this approach. Here, we derive a simple thermodynamic model that describes how a super-additive response can occur, even for two very similar ligands. We discuss its implications for the specific case of cysteine-derived compounds and the treatment of opioid withdrawal symptoms and suggest avenues by which it could be tested experimentally.