An investigation of bisphosphonate inhibition of a vacuolar proton-pumping pyrophosphatase

We report the results of a three-dimensional quantitative structure-activity relationship (3D-QSAR)/comparative molecular field analysis (CoMFA) of the activity of 18 bisphosphonates and imidodiphosphate in the inhibition of a mung bean (Vigna radiata L.) vacuolar proton pumping pyrophosphatase (V/H⁺-PPase; EC 3.6.1.1). We find an experimental versus QSAR predicted pK_i^app R² value of 0.89, a cross-validated R²=0.77, and a bootstrapped R²=0.89 for 18 bisphosphonates plus imidodiphosphate over the 1.3 μM to 425 μM range of K_i^app values. We also demonstrate that this approach has predictive utility (a 0.26 pK_i^app rms error for three test sets of 3 activity predictions each), corresponding to about a factor of two error in K_i^app prediction. The 3D-QSAR/CoMFA approach provides a quantitative method for predicting the activity of V/H⁺-PPase inhibitors and is likely to be of use in the design of novel pharmacological agents since all of the major human disease-causing parasitic protozoa contain large levels of pyrophosphate, together with V-type proton-pumping pyrophosphatases located in plant-like vacuoles (acidocalcisomes), which are absent in their mammalian hosts.