| The goal of this research is to establish new drug targets and inhibitors against pathogens responsible for tropical and infectious diseases. Farnesyl diphosphate synthase, which forms farnesyl diphosphate in the isoprenoid biosynthesis pathway, is an exciting new drug target because of its central role in a diverse array of biochemical pathways. Farnesyl diphosphate is a precursor in the synthesis of sterols, ubiquinones, dolichol, heme A, and a variety of carotenoids in plants. It is also the precursor for the condensation reaction to form dehydrosqualene by dehydrosqualene synthase, which finally forms the virulence factor staphyloxanthin in Staphylococcus aureus. Bisphosphonates, currently used to treat osteoporosis, have also been found to inhibit the formation of farnesyl diphosphate by binding to the farnesyl diphosphate synthase enzyme. Bisphosphonates are also interesting in context of cancer immunotherapy since they stimulate gammadelta T cells of the immune system, inhibit tumor growth, have anti-parasitic, antibacterial, and herbicidal activity. I have used solid state NMR spectroscopy as a tool to obtain structural information on the binding of inhibitors like bisphosphonates and phosphonosulfonates to their enzyme targets. Since bisphosphonates have been used primarily as osteoporosis drugs, I have performed solid state NMR and calorimetric studies to investigate the static and dynamic structures of bisphosphonates bound to bone. I also initiated preliminary research on the interaction of lipids and sterols in bilayers to pave the way for better understanding the transport of drugs through cell membranes. The results of this research will help in the design of novel inhibitors that selectively bind to their enzyme targets while having low affinity towards human bone. |
