Density functional theory calculation of interaction between bisphosphate and farnesyl pyrophosphate synthase

Abstract

Bisphosphonates (BPs) are the most widely used and effective treatment for osteoporosis and Pagets disease of the bone. To date, a number of BPs-namely alendronate, risedronate, and minodronate-have been launched to market. Nitrogen-BPs (N-BPs) act by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS), and several crystal structures of complexes between FPPS and N-BPs have been identified. Understanding the physical basis of the binding between proteins and small molecules is an important goal in both medicinal chemistry and structural biology. Here, we conducted density functional theory calculations for BPs and their surrounding residues and were able to successfully reproduce experimental results qualitatively. In addition, we found that both the side chain and backbone of Phe 99 are important for binding between minodronate and FPPS, suggesting that the strong activity of minodronate comes from its interaction with Phe 99, which alendronate and risedronate lack.