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Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists.

ABSTRACT: 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.

SUBMITTER: Koes D

PROVIDER: S-EPMC3299697 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists.

Koes David D Khoury Kareem K Huang Yijun Y Wang Wei W Bista Michal M Bista Michal M Popowicz Grzegorz M GM Wolf Siglinde S Holak Tad A TA Dömling Alexander A Camacho Carlos J CJ

PloS one 20120312 3

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 r ...[more]

PMID: 22427896

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Project description:This study presents an analysis of the small molecule bioactivity profiles across large quantities of diverse protein families represented in PubChem BioAssay. We compared the bioactivity profiles of FDA approved drugs to non-FDA approved compounds, and report several distinct patterns characteristic of the approved drugs. We found that a large fraction of the previously reported higher target promiscuity among FDA approved compounds, compared to non-FDA approved bioactives, was frequently due to cross-reactivity within rather than across protein families. We identified 804 potentially novel protein target candidates for FDA approved drugs, as well as 901 potentially novel target candidates with active non-FDA approved compounds, but no FDA approved drugs with activity against these targets. We also identified 486348 potentially novel compounds active against the same targets as FDA approved drugs, as well as 153402 potentially novel compounds active against targets without active FDA approved drugs. By quantifying the agreement among replicated screens, we estimated that more than half of these novel outcomes are reproducible. Using biclustering, we identified many dense clusters of FDA approved drugs with enriched activity against a common set of protein targets. We also report the distribution of compound promiscuity using a Bayesian statistical model, and report the sensitivity and specificity of two common methods for identifying promiscuous compounds. Aggregator assays exhibited greater accuracy in identifying highly promiscuous compounds, while PAINS substructures were able to identify a much larger set of "middle range" promiscuous compounds. Additionally, we report a large number of promiscuous compounds not identified as aggregators or PAINS. In summary, the results of this study represent a rich reference for selecting novel drug and target protein candidates, as well as for eliminating candidate compounds with unselective activities.

Dataset Information

Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists.

Publications

Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists.

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