Computational approaches to antibacterial and antimalarial hit finding

COMP 214

A. Peter Johnson, P.Johnson@leeds.ac.uk1, Colin W. G. Fishwick, C.W.G.Fishwick@leeds.ac.uk1, Glenn A. McConkey, G.A.McConkey@leeds.ac.uk2, Timo Heikkila3, Matthew Davies1, Deborah Cowan1, and Anil Agarwal1. (1) School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom, (2) Faculty of Biological Sciences, University of Leeds, United Kingdom, (3) Facullty of Biological Sciences, University of Leeds, United Kingdom
Malaria and tuberculosis are major causes of mortality in developing countries, a situation exacerbated by the emergence of species resistant to current therapies. Structure based approaches have been applied to the design of inhibitors of the essential enzymes (a) dihydroorotate dehydrogenase from P. falciparum and (b) bacterial RNA polymerase, the target of tuberculosis therapy using analogues of rifamycin. De novo design (SPROUT) and virtual high throughput screening (eHITS) led to a series of ligand structures, a small number of which were synthesised or purchased as appropriate and subjected to biological assay which identified several low micromolecular inhibitors. Structure based hit optimisation (using SPROUT LeadOpt) provided compounds with increased inhibitory activity. The higher than usual success rate achieved in the virtual high throughput screening approach is attributed to the accuracy and conservatism of the eHITS scoring function. Details of the computational and experimental techniques and results will be presented.
 

Drug Discovery
1:00 PM-4:10 PM, Thursday, March 26, 2009 Salt Palace Convention Center -- 257, Oral

Division of Computers in Chemistry

The 237th ACS National Meeting, Salt Lake City, UT, March 22-26, 2009