Identification of selective protein-protein interaction inhibitors using efficient in silico peptide-directed ligand design

Beekman, Andrew M., Cominetti, Marco M. D., Walpole, Samuel J., Prabhu, Saurabh, O'Connell, Maria A., Angulo Alvarez, Jesus and Searcey, Mark (2019) Identification of selective protein-protein interaction inhibitors using efficient in silico peptide-directed ligand design. Chemical Science, 10 (16). pp. 4502-4508. ISSN 2041-6520

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    Abstract

    The development of protein-protein interaction (PPI) inhibitors with therapeutic value is of increasing importance as the first clinical agent has now been approved, but PPIs remain difficult targets for the development of small molecule ligands. This article describes a highly efficient approach to the development of inhibitors of the p53/hDMX or hDM2 interaction that involves the design of small molecules in silico based upon a peptide/protein structure. The process for molecule design, starting from a virtual library of just over 1200 fragments, led to the eventual synthesis of twenty compounds, of which ten bound to either hDM2, hDMX or both in vitro binding assays. This 50% success rate is extremely efficient compared to traditional high throughput screening. The identification of two selective hDMX inhibitors from twenty compounds highlights this efficiency as, to date, only two other hDMX-selective agents exist in the literature. Preliminary biological studies show that 20% of the compounds identified have cellular activity and activate downstream pathways associated with p53 activation.

    Item Type: Article
    Faculty \ School: Faculty of Science > School of Pharmacy
    Faculty of Science > School of Chemistry
    Faculty of Science
    Depositing User: LivePure Connector
    Date Deposited: 12 Mar 2019 14:30
    Last Modified: 16 May 2019 07:31
    URI: https://ueaeprints.uea.ac.uk/id/eprint/70209
    DOI: 10.1039/C9SC00059C

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