Biophysical Society Thematic Meeting - November 16-20, 2015

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts

Insights into Molecular Switch: Crystal Structure Analysis of Wild Type and Fast Hydrolyzing Mutant of EhRabX3, a Tandem Ras Superfamily GTPase from Entamoeba Histolytica Mintu Chandra 1 , Vijay K. Srivastava 1 , Yumiko S. Nakano 2 , Tomoyoshi Nozaki 2 .Sunando Datta 1 , 1 Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, Indiana, India, 2 National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Shinjuku-ku, Tokyo, Japan. See abstract: 22-POS Board 22

Moving Forward New Medicines and New Targets in Malaria Timothy Wells . Medicines for Malaria Venture, Geneva, Switzerland.

Drug discovery in malaria in the last decade has been built on two pillars and both of these have shown success for some of the projects we have been collaborating on. First, structure-based drug design has been used to optimize new molecules. Using the three dimensional structures of dihydrofolate reductase new inhibitors have been designed to overcome resistance, and the structure of dihydro-orotate dehydrogenase new classes of compound have been optimized which are active against the parasite both in vitro, and in studies in patients and volunteers. On the other hand, technological developments in phenotypic screening mean that almost 6 million compounds have now been screened directly against the parasite. This has yielded several new membrane bound targets, including the sodium channel PfATP4 and the lipid kinase PI4-kinase. These represent high value targets for structural evaluation, and for structure based optimization, especially if such models can be used to suggest new chemical scaffolds. The other output from this process has been the availability of a collection of high value hits, called Malaria Box which has been used as a test set by several groups to understand better the pharmacological impact of these compounds on the parasite.

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