An Investigation of Bone Resorption and Dictyostelium discoideum Growth Inhibition by Bisphosphonate Drugs

We report the results of 3D-QSAR/CoMFA investigations of the activity of bisphosphonate drugs, farnesyl pyrophosphate synthase (FPPSase) inhibitors, in the inhibition of bone resorption as well as the growth of Dictyostelium discoideum. In the case of D. discoideum, we find an experimental versus QSAR predicted pIC50 R2 value of 0.94 for 16 bisphosphonates over the 9−1200 μM range of IC50 values, a cross-validated R2 = 0.90, and a bootstrapped R2 = 0.94, and we demonstrate that this approach has predictive utility (a 0.18 pIC50 rms error for three test sets of 3 predictions). In bone resorption, we find an experimental versus predicted pLED (lowest effective dose) R2 = 0.79 for 35 bisphosphonates over the 0.0001−1 mg of P/kg LED range, a cross-validated R2 = 0.75, and a bootstrapped R2 = 0.79. Two sets of 31 compounds were used as training sets for the predicted pLED values for two sets of 4 compounds which have an rms error of 0.44, larger than that found with D. discoideum. However, this can be attribut...