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

Koes, D and Khoury, K and Huang, Y and Wang, W and Bista, M and Popowicz, GM and Wolf, S and Holak, TA and Dömling, A and Camacho, CJ (2012) Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists. PLoS ONE, 7 (3).

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Koes, Ddkoes@pitt.eduDKOES0000-0002-6892-6614
Khoury, K
Huang, Y
Wang, Wwangwei3@pitt.eduWANGWEI3
Bista, M
Popowicz, GM
Wolf, S
Holak, TA
Dömling, A
Camacho, CJccamacho@pitt.eduCCAMACHO
ContributionContributors NameEmailPitt UsernameORCID
Date: 12 March 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0032839
Schools and Programs: School of Medicine > Computational and Systems Biology
School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
MeSH Headings: Chemistry, Pharmaceutical--methods; Crystallography; Drug Discovery--methods; Internet; Protein Interaction Mapping--methods; Proto-Oncogene Proteins c-mdm2--antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2--chemistry; Small Molecule Libraries; Software; Systems Biology--methods; Systems Biology--trends; Tumor Suppressor Protein p53--antagonists & inhibitors; Tumor Suppressor Protein p53--chemistry
Other ID: NLM PMC3299697
PubMed Central ID: PMC3299697
PubMed ID: 22427896
Date Deposited: 13 Sep 2012 20:25
Last Modified: 05 Feb 2019 15:55


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