The ligand paradox between affinity and efficacy: can you be there and not make a difference?

Efficacy is described in terms of the ligand-induced bias of receptor micro-conformations. A virtual simulation of binding of a collection of random ligands can reconcile an apparent paradox in receptor theory, namely the theoretical requirement that affinity and efficacy be related to each other and the experimental fact that medicinal chemistry often can separate structure-activity relationships for affinity and efficacy. The simulation indicates that homoscedacity in the relationship allows for a general correlation with isolated instances of non-compliance. This leads to the conclusion that if a ligand binds to the receptor it will change the receptor by its presence. Therefore, this suggests that all ligands with macro-affinity should be extensively studied for pharmacological activities other than simple G-protein activation with the potential promise of discovering new therapeutic applications for old drugs.