Abstract

Zoledronic acid (ZA) is a third-generation heterocyclic nitrogen-containing bisphosphonate approved in the EU for the treatment of Paget’s disease of bone. Like other nitrogen-containing bisphosphonates such as pamidronic acid (PMD). ZA is a more potent inhibitor of bone resorption than bisphosphonates that do not contain nitrogen e.g. etidronic acid, clodronic acid (CLD) and tiludronic acid. In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to obtain information on relative toxicity of ZA, CLD and PMD. The results of the analyses show that ZA, CLD and PMD have LUMO-HOMO energy differences of the order of 6.1 to 7.0 eV so that the compounds would all be inert kinetically. The molecular surfaces of ZA, CLD and PMD are found to abound in neutral green and electron-rich red and yellow regions so that they can be subject to lyophilic and electrophilic attacks. Paucity of electron-deficient regions on the molecular surfaces of the compounds indicate that the compounds may not induce cellular toxicity associated with glutathione depletion and DNA damage associated with oxidation of nucleobases in DNA.