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 22.214.171.124). We find an experimental versus QSAR predicted pKiapp 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 Kiapp values. We also demonstrate that this approach has predictive utility (a 0.26 pKiapp rms error for three test sets of 3 activity predictions each), corresponding to about a factor of two error in Kiapp 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.
|Original language||English (US)|
|Number of pages||6|
|Journal||Biochemical and Biophysical Research Communications|
|State||Published - Sep 21 2001|
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology