Modification of the R side chain on bisphosphonates is very minor today, single hydroxyl group at that position seems to give the best results in terms of activity. The hydroxyl group plays a role in forming a water-induced bond with glutamine (Gln240) on the target enzyme. Drugs that have no hydroxyl group initially cause better inhibition than parent compounds, without hydroxyl group the drug seems to fit more easily into the open active site. The absence of hydroxyl group however reduces the ability to hold the target enzyme complex in isomerized state. Biological activity of bisphosphonates with hydroxyl group, therefore, appears over longer time.