This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Bosch lab is interested in proteins enabling the malaria parasite Plasmodium falciparum to invade or escape from human liver- and red blood cells as well as Mosquito vector midgut cells. By structure based drug design in conjunction with X-ray crystallography, we seek to identify and optimize small molecules which will inhibit the functions of key enzymes and their interaction with essential partner proteins, thus impairing the parasite's ability to proliferate. Through virtual library compound screening, we already found promising candidates specific for P. falciparum Aldolase. A subset of 60 low molecular weight compounds was enzymatically and biophysically characterized, before attempting co-crystallization. Meanwhile, we obtained structures of three ligands bound to the expected region of Aldolase and are pursuing further structure activity relationship studies with derivatives of those initial hits.
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