Developing new chemotherapeutic agents against bone resorption and parasitic diseases through computer-aided drug design.

摘要

According to the World Health Organization's 2004 World Health Report, several million people are infected by parasitic diseases and 1.4 million of them die annually in Africa, South America and parts of the Middle East. The drugs currently used to combat parasitic diseases such as African sleeping sickness and malaria, caused by Trypanosoma brucei and Plasmodium falciparum respectively, are very old and have terrible side effects. New, more effective drugs with fewer side effects need to be discovered. Bisphosphonates, which are currently used against bone resorption diseases, have been found to inhibit the growth of several parasitic protozoa, causative agents of a variety of parasitic diseases. They do that by inhibiting a number of enzymes important for the growth of the parasites but not as important or nonexistent in the human host.; The use of bisphosphonates, analogs of diphosphate biomolecules, as inhibitors of pyrophosphate-utilizing and phosphoryl-transfer enzymes has been explored in this work using ligand-based drug design. Quantitative Structure-Activity Relationships (QSAR) methods such as Comparative Molecular Field Analysis, Comparative Molecular Similarity Indices Analysis and Pharmacophore modeling were developed in an attempt to correlate structural or property descriptors of compounds such as hydrophobicity, topology, electronic properties, and steric effects with the compounds' activities. They only use information about the ligands that bind to a particular enzyme (structure and biological activity) and not the actual binding site or the enzyme itself whose structure may not be known yet.; Using the above mentioned 3D-QSAR methods we have developed predictive models of the inhibition of human farnesyl pyrophosphate synthase (FPPS), important for osteoclast function and survival as well as Trypanosoma brucei FPPS, soluble vacuolar pyrophosphatase and phosphoglycerate kinase, all important for the proliferation of Trypanosoma brucei, the causative agent of African sleeping sickness. These predictive models aid in optimizing existing inhibitors and ultimately designing novel ones.