An effective molecular design successfully captures the balance, proportion and rhythm of a specific biomolecule while respecting the unity of the biomolecule with its cellular, tissue, whole organism and ecological surroundings. I propose to lead the design of a drug that crosslinks two proteins of the gliding motility machinery of P. falciparum: the causative agent of malaria. This molecule will be a novel malaria treatment operating directly at the complicated host-pathogen interface and influencing the enormous global health burden of this disease. First, the inter-locking parts of the gliding motility machinery will be visualized by a combination of novel molecular modeling approaches and X-ray crystallography. Of note, three- dimensional visualization of the first interlocking part failed via either of these approaches separately, but we succeeded by cleverly deploying them in an integrated fashion. Additional interlocking pieces of the gliding motility machine are already being unveiled by this unique approach, so we are confident that we can visualize the intricacies of a large bloc of the molecular machine in its in situ configuraion. Second, exploitable pockets in the whole machine will be targeted for drug design via a combination of in silico screening of chemical databases and novel cheminformatics techniques. We describe how this integrated approach revealed a hitherto unrecognized """"""""druggable"""""""" site, allowing the biology to guide the design.
Showing the most recent 10 out of 26 publications
