title: 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.
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Koes
authors.forename: Kareem
authors.initials: K
authors.lastname: Khoury
authors.forename: Yijun
authors.initials: Y
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Michal
authors.initials: M
authors.lastname: Bista
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Popowicz
authors.forename: Siglinde
authors.initials: S
authors.lastname: Wolf
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Camacho
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003461:Crystallography; D055808:Drug Discovery / Q000379:methods*; D020407:Internet; D025941:Protein Interaction Mapping / Q000379:methods*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D054852:Small Molecule Libraries; D012984:Software; D049490:Systems Biology / Q000379:methods* / Q000639:trends; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2