Home > Archives > Additional Archives > Art Olson   Art Olson Dept of Molecular Biology The Scripps Research Institute La Jolla, CA 92093 olson@scripps.edu http://www.scripps.edu/pub/olson-web/   Abstract: We have developed a new computational approach to simulating the evolution of drug resistance and screening drug candidates in silico for robustness in the face of resistance mutations. The approach is based upon the use of co-evolutonary algorithms to test and rank competing populations of trial drugs and mutant drug targets [Rosen, 1999a]. We have been using the extensive structural and clinical data on the HIV protease system to test and validated the approach. Our first series of computations used a simplified volume based measure of viral viability to allow the virtual screening of millions of possible drugs against millions of possible mutants[Rosen, 2000b]. Recent work has focused on more detailed models for drug-target interactions to aid in our understanding and prediction of clinical development of drug resistant strains. We have been able to use our methods to "predict" the protease active site mutations that have been observed in clinical isolates from the FDA approved drug therapies, and to suggest structural modifications to these drugs to make them more robust [Stoffler, 2001]. Our latest effort involves extending these approaches with a fully detailed atomic model by using our AutoDock flexible drug docking in a massively parallel computational environment. In collaboration with Entropia, we have established an internet-based community (currently over 20,000 individuals) who have donated their computers to run our docking computations on HIV-protease drug screening (FightAids@Home). With the orders of magnitude more computing power, we anticipate the development of extended novel methodologies, as well as greatly improved modeling results. Rosin, C.D., Belew, R.K., Morris, G.M., Olson, A.J. (1999) Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease. Proc. Natl. Acad. Sci. USA 96:1369-1374. Rosin, C., Belew, R., Walker, W., Morris, G., Olson, A., Goodsell, D.S. (1999) Coevolution and subsite decomposition for the design of resistance-evading HIV1 protease inhibitors. J. Mol. Biol. 287(1):77-92. Stoffler, D., Sanner, M., Morris, G.M., Olson, A.J., Goodsell, D. (2001) Evading HIV-1 protease drug resistance. Submitted, J. Mol. Biol.
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