Thermodynamics of Bisphosphonates Binding to Human Bone: A Two-Site Model

We have used isothermal titration calorimetry (ITC) to study the thermodynamics of binding of 12 bisphosphonates to human bone. The ITC results show that there are two binding sites. Site A is the weak, highly populated site seen by NMR and is characterized by an average Delta G of binding of -5.2 kcal. Site B is a strong binding site characterized by a Delta G of binding of -8.5 kcal. Binding to both sites is overwhelmingly entropy driven. Using a thermodynamic group approach and a linear regression method, we predict the Delta G of binding of all 12 compounds with an R-2 = 0.95 (a 0.19 kcal error variance estimate, similar to 3% of the total Delta G range), opening up the way to designing novel chemotherapy, immunotherapy, and anti-infectious disease drugs having weak bone binding affinity.