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 DeltaG of binding of -5.2 kcal. Site B is a strong binding site characterized by a DeltaG 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 DeltaG of binding of all 12 compounds with an R(2) = 0.95 (a 0.19 kcal error variance estimate, approximately 3% of the total DeltaG range), opening up the way to designing novel chemotherapy, immunotherapy, and anti-infectious disease drugs having weak bone binding affinity.
Mukherjee
Sujoy
S
Center for Biophysics & Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Huang
Cancan
C
Guerra
Francisco
F
Wang
Ke
K
Oldfield
Eric
E
D001842:Bone and Bones / Q000737:chemistry* / Q000378:metabolism; D002151:Calorimetry / Q000379:methods; D004164:Diphosphonates / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D008956:Models, Chemical; D013816:Thermodynamics
D004164:Diphosphonates