Rational drug design for neglected diseases: Implementation of computational methods to construct predictive devices and examine mechanisms .

摘要

Over a billion individuals worldwide suffer from neglected diseases. This equates to approximately one-sixth of the human population. These infections are often endemic in remote tropical regions of impoverished populations where vectors can flourish and infected individuals cannot be effectively treated due to a lack of hospitals, medical equipment, drugs, and trained personnel. The few drugs that have been approved for the treatments of such illnesses are not widely used because they are riddled with inadequate implications of cost, safety, drug availability, administration, and resistance. Hence, there exists an eminent need for the design and development of improved new therapeutics. Influential world-renowned scientists in the Consortium for Parasitic Drug Development (CPDD) have preformed extensive biological testing for compounds active against parasites that cause neglected diseases. These data were acquired through several collaborations and found applicable to computational studies that examine quantitative structure-activity relationships through the development of predictive models and explore structural relationships through docking. Both of these in silico tools can contribute to an understanding of compound structural importance for specific targets. The compilation of manuscripts presented in this dissertation focus on three neglected diseases: trypanosomiasis, Chagas disease, and leishmaniasis. These diseases are caused by kinetoplastid parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp., respectively. Statistically significant predictive devices were developed for the inhibition of the: (1) T. brucei P2 nucleoside transporter, (2) T. cruzi parasite at two temperatures, and (3) two species of Leishmania. From these studies compound structural importance was assessed for the targeting of each parasitic system. Since these three parasites are all from the Order Kinetoplastida and the kinetoplast DNA has been determined a viable target, compound interactions with DNA were explored to gain insight into binding modes of known and novel compounds.;Index words. Trypanosomiasis, Leishmaniasis, Chagas Disease, Nucleoside transporter, DNA, Molecular Modeling, 3D-QSAR, CoMFA, CoMSIA, Docking.