Presenting the Promising New Results to the Public

Two new papers that have depended on the results of FightAIDS@Home have now been submitted for
publication. Titles and descriptions are as follows:

“Interleaved virtual and experimental screening for HIV protease inhibitors”
Max W. Chang, Michael J. Giffin, William M. Lindstrom, Arthur J. Olson, Richard K. Belew, and
Bruce E. Torbett
Searching for HIV protease inhibitors in a large, random collection of chemical compounds requires
expensive machinery and other materials. Even then, the odds of finding a promising “hit” are low—
somewhere between 1/1,000 and 1/10,000. One alternative is the use of virtual screening, which can
select likely inhibitors based on computer modeling. This allows experimental testing of a much smaller
set of compounds. However, potential inhibitors selected through virtual screening may have undesirable
properties that make them difficult to test experimentally or that make them poor drug candidates.
To improve the chances of finding promising inhibitor candidates, we took advantage of a large chemical
library that had already been tested against HIV (i.e. the “DTP moderately-active library”).
Approximately 1,500 compounds were found to provide some protection for human cells against HIV
infection, although these compounds could target any part of the virus, or even something present in
human cells. We used AutoDock to screen virtually these compounds
against a wild-type HIV protease structure, and we incorporated the previously published
FightAIDS@Home work1 to choose 36 candidates. After experimental testing with HIV protease, we
were able to confirm 5 of these compounds as inhibitors. While these new inhibitors are not nearly as
potent as FDA-approved drugs, this approach has proven to be useful in finding new inhibitors with a
relatively small amount of work in the “wet lab.” We look forward to extending this work in further
screens against HIV protease mutants and other targets.

“Combining molecular docking and sequence analysis to predict resistance mutations for novel
inhibitors of HIV protease”
Max W. Chang, Michael J. Giffin, Ying-Chuan Lin, John H. Elder, Arthur J. Olson, Bruce E.
Torbett, Richard K. Belew
Current anti-HIV drugs often become less potent over time because of the development of drug resistance
mutations. In many cases, these mutations in HIV affect multiple drugs, making all of them less useful.
As newer drugs are being developed, it would be helpful to be able to (1) predict likely mutations that
might lower a drug’s potency and (2) focus on potential drugs which are not affected by existing and
predicted drug resistance mutations. We used structural modeling based on AutoDock and our previous
work with FAAH to predict three resistance mutations against a new inhibitor called AB2. Using
molecular biology techniques, we synthesized HIV protease mutants with every combination of these
mutations, and then we tested their resistance against AB2. We found higher resistance as the number of
mutations increased, indicating that our predictions were correct. As this technique is refined, we hope to
apply it to the best compounds produced from the FightAIDS@Home research and directly address drug
resistance during the early stages of drug design.
We could not perform this research without your help. Thank you very much for
helping us advance the fight against multi-drug-resistant “super bugs” of HIV and
for helping us improve the tools and techniques used in the entire
field of structure-based drug design.