Dataset Information

Chemical Space Overlap with Critical Protein-Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries.

ABSTRACT: There is growing interest in the use of structure-based virtual screening to identify small molecules that inhibit challenging protein-protein interactions (PPIs). In this study, we investigated how effectively chemical library members docked at the PPI interface mimic the position of critical side-chain residues known as "hot spots". Three compound collections were considered, a commercially available screening collection (ChemDiv), a collection of diversity-oriented synthesis (DOS) compounds that contains natural-product-like small molecules, and a library constructed using established reactions (the "screenable chemical universe based on intuitive data organization", SCUBIDOO). Three different tight PPIs for which hot-spot residues have been identified were selected for analysis: uPAR?uPA, TEAD4?Yap1, and CaV ??CaV ?. Analysis of library physicochemical properties was followed by docking to the PPI receptors. A pharmacophore method was used to measure overlap between small-molecule substituents and hot-spot side chains. Fragment-like conformationally restricted small molecules showed better hot-spot overlap for interfaces with well-defined pockets such as uPAR?uPA, whereas better overlap was observed for more complex DOS compounds in interfaces lacking a well-defined binding site such as TEAD4?Yap1. Virtual screening of conformationally restricted compounds targeting uPAR?uPA and TEAD4?Yap1 followed by experimental validation reinforce these findings, as the best hits were fragment-like and had few rotatable bonds for the former, while no hits were identified for the latter. Overall, such studies provide a framework for understanding PPIs in the context of additional chemical matter and new PPI definitions.

SUBMITTER: Si Y

PROVIDER: S-EPMC7175409 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Chemical Space Overlap with Critical Protein-Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries.

Si Yubing Y Xu David D Bum-Erdene Khuchtumur K Ghozayel Mona K MK Yang Baocheng B Clemons Paul A PA Meroueh Samy O SO

ChemMedChem 20181220 1

There is growing interest in the use of structure-based virtual screening to identify small molecules that inhibit challenging protein-protein interactions (PPIs). In this study, we investigated how effectively chemical library members docked at the PPI interface mimic the position of critical side-chain residues known as "hot spots". Three compound collections were considered, a commercially available screening collection (ChemDiv), a collection of diversity-oriented synthesis (DOS) compounds t ...[more]

PMID: 30548204

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Dataset Information

Chemical Space Overlap with Critical Protein-Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries.

Publications

Chemical Space Overlap with Critical Protein-Protein Interface Residues in Commercial and Specialized Small-Molecule Libraries.

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