TY  - JOUR
ID  - pittir14153
UR  - http://d-scholarship-dev.library.pitt.edu/14153/
IS  - 3
A1  - Koes, D
A1  - Khoury, K
A1  - Huang, Y
A1  - Wang, W
A1  - Bista, M
A1  - Popowicz, GM
A1  - Wolf, S
A1  - Holak, TA
A1  - Dömling, A
A1  - Camacho, CJ
Y1  - 2012/03/12/
N2  - Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. © 2012 Koes et al.
JF  - PLoS ONE
VL  - 7
TI  - Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists
AV  - public
ER  -