To a first approximation, the optimal degree of conformational pre-organization for strong binding is achieved when a compound is rigidly locked in the bound conformation. In this case, there is no conformational entropy cost to binding as there are no other conformational states available to the compound. Moreover, there is no strain in the bound compound because all ligand atoms are pre-positioned to optimally engage the binding site on the protein. We note that a fully rigid ligand may not be ideal in practice if elements of flexibility are required to achieve good binding kinetics. However, such kinetic effects are not relevant to the equilibrium binding affinity which is the topic here.