High-throughput Direct Structural Screening for Drug Lead Compounds

U.S. Government personnel deployed in tropical and neotropical regions continue to be at risk for developing malaria. Drug resistant malaria parasites are becoming more common in these areas, increasing the risk of American personnel developing a serious, life-threatening disease. Cross resistance between drugs is becoming much more common. Due to the emergence of drug resistance, derivates of known anti-malarial drug classes are not long term solutions. Faced with the realities of the malaria threat, novel, unbiased technologies are required to prime the drug discovery programs. High-throughput techniques for lead compound generation are well known, but these techniques tend to be too expensive for use on tropical diseases, which do not affect rich populations. New techniques to bring down the costs are required. A method for measuring small molecules and molecule fragments will make tropical disease cures more affordable, and therefore allow the possibility of cures. This project will demonstrate the ability to of X-ray techniques to detect the interactions of cycloguanil, a known dihydrofolate reductase inhibitor, with wild-type and quadruple mutant P. falciparium DHFR-TS. This project will demonstrate automated x-ray data collection and processing to demonstrate the complete direct screening technology package.