Crystallization, X-Ray Structure Determination and Structure-Based Drug Design for Targeted Malarial Enzymes

摘要

Malaria poses major threat to public health worldwide. The situation is worsened by the rapid emergence of strains resistant to existing drugs. There is a tremendous need to develop new potent drugs for combating this disease. It is therefore important identify novel target pathways or enzymes in the parasite that is essential for the survival and growth of the parasite. Moreover, the targets have to be different in biochemically and structurally so that they present enough selectivity. During the intraerythrocytic stage, glycolysis serves as the major energy producing mechanism for the parasite. LDH, the last enzyme in this pathway, is apparently essential for the survival of Plasmodium falciparum, the most lethal strain of human malaria parasite. In this project we explore the possibility that P falciparum LDH could be used as a target for developing anti-parasitic agent. Our approach involves high throughput screening of diverse combinatorial library and structure-based design. The high throughput screening effort (40,00 compound diverse representative library) has produced several hits which will be tested further analyzed by in vitro enzyme assay and anti-parasitic activity in parasite culture. Selected compounds will be used for structure analysis that will guide further synthesis. Molecular modeling has also produced some interesting results that are presently being tested. We have also expressed, purified, crystallized a new enzyme of the glycolytic pathway which will be studied by X-ray diffraction method.