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 α⋅CaV β. 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.
Keywords:
compound libraries; computational chemistry; protein-protein interactions; virtual screening.
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / metabolism
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Biological Products / chemical synthesis
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Biological Products / chemistry
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Biological Products / pharmacology*
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Calcium Channels / chemistry
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Calcium Channels / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Humans
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Molecular Structure
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Muscle Proteins / antagonists & inhibitors
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Muscle Proteins / chemistry
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Muscle Proteins / metabolism
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / chemistry
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Phosphoproteins / metabolism
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Protein Binding
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Protein Interaction Mapping
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Receptors, Urokinase Plasminogen Activator / antagonists & inhibitors
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Receptors, Urokinase Plasminogen Activator / chemistry
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Receptors, Urokinase Plasminogen Activator / metabolism
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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TEA Domain Transcription Factors
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / chemistry
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Transcription Factors / metabolism
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Urokinase-Type Plasminogen Activator / antagonists & inhibitors
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Urokinase-Type Plasminogen Activator / chemistry
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Urokinase-Type Plasminogen Activator / metabolism
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Biological Products
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Calcium Channels
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DNA-Binding Proteins
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Muscle Proteins
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Phosphoproteins
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Receptors, Urokinase Plasminogen Activator
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Small Molecule Libraries
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TEA Domain Transcription Factors
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TEAD4 protein, human
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Transcription Factors
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YAP-Signaling Proteins
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YAP1 protein, human
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Urokinase-Type Plasminogen Activator