Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase

K.      Ohno; K.      Mori; M.      Orita; M.      Takeuchi

Abstract

Bisphosphonates (BPs) are the most widely used and effective treatment for osteoporosis and Pagets disease. Non-nitrogen containing BPs (non-N-BPs), namely etidronate, clodronate, tiludronate, as well as nitrogen-containing BPs (N-BPs), namely pamidronate, alendronate, ibandronate, risedronate, zoledronate and minodronate have been launched on the market to date. N-BPs act by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS), and several crystal structures of complexes between FPPS and N-BPs have been revealed. Understanding the physical basis of the binding between protein and small molecules is an important goal in both medicinal chemistry and structural biology. In this review, we analyze in detail the energetic basis of molecular recognition between FPPS and N-BPs. First, we summarize the interactions between ligands and proteins observed in N-BPs-FPPS complexes in the Protein Data Bank (PDB). Second, we present an interaction energy analysis on the basis of full quantum mechanical calculation of FPPS and N-BP complexes using the fragment molecular orbital (FMO) method. The FMO result revealed that not only hydrogen bond and electrostatic interaction but also CH-O and π-πinteraction with FPPS are important for N-BPs potency. Third, we describe a binding site analysis of FPPS on the basis of the inhomogeneous solvation theory which, by clustering the results from an explicit solvent molecular dynamics simulation (MD), is capable of describing the entropic and enthalpic contributions to the free energies of individual hydration sites. Finally, we also discuss the structure-activity relationship (SAR) of the series of minodronate derivatives.

Keywords: Bisphosphonate, farnesyl pyrophosphate synthase, bone resorption, osteoclast, protein-ligand binding, drug design, Bisphosphonates (BPs), osteoporosis, Paget's disease, pamidronate, alendronate, ibandronate, risedronate, zoledronate, minodronate, Minodronic acid, tiludronate, adenosine triphosphate, mevalonate pathway, isopentenyl pyrophosphate, isothermal titration calorimetry, enthalpy-driven, Protein Data Bank, fragment molecular, isoprenyl synthases, quantum mechanics, ibandronate model, electrostatic, dispersion, imidazopyrizine, antiresoptive activity, Charge transfer plus higher-order mixed terms, Geranyl Pyrophosphate, Nitrogen-containing BPs