An Investigation of Bisphosphonate Inhibition of a Vacuolar Proton-Pumping Pyrophosphatase

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• 作者：Szabo ; Christina M. ; Oldfield ; Eric
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2001
• 出版时间：September 21, 2001
• 年：2001
• 卷：287
• 期：2
• 页码：468-473
• 全文大小：115 K

文摘

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^app_i 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^app_i values. We also demonstrate that this approach has predictive utility (a 0.26 pK^app_i rms error for three test sets of 3 activity predictions each), corresponding to about a factor of two error in K^app_i 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.