New insights into human farnesyl pyrophosphate synthase inhibition by second-generation bisphosphonate drugs.

Pamidronate, alendronate, APHBP and neridronate are a group of drugs, known as second-generation bisphosphonates (2G-BPs), commonly used in the treatment of bone-resorption disorders, and recently their use has been related to some collateral side effects. The therapeutic activity of 2G-BPs is related to the inhibition of the human Farnesyl Pyrophosphate Synthase (hFPPS). Available inhibitory activity values show that 2G-BPs act time-dependently, showing big differences in their initial inhibitory activities but similar final IC values. However, there is a lack of information explaining this similar final inhibitory potency. Although different residues have been identified in the stabilization of the R side chain of 2G-BPs into the active site, similar free binding energies were obtained that highlighted a similar stability of the ternary complexes, which in turns justified the similar IC values reported. Free binding energy calculations also demonstrated that the union of 2G-BPs to the active site were 38 to 54 kcal mol energetically more favourable than the union of the natural substrate, which is the basis of the inhibition potency of the hFPPS activity.