Chemical Space Overlap with Critical Protein–Protein Interface Residues in Commercial and Specialized Small‐Molecule Libraries

Citations Over TimeTop 24% of 2018 papers

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 Ca_V α⋅Ca_V 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.

Related Papers

• → Novel Approach for Efficient Pharmacophore-Based Virtual Screening: Method and Applications(2009)140 cited
• → Molecular docking, pharmacophore based virtual screening and molecular dynamics studies towards the identification of potential leads for the management of H. pylori(2019)12 cited
• → Docking compared to 3D-pharmacophores: the scoring function challenge(2010)37 cited
• → Structure-based virtual screening for identification of novel 11β-HSD1 inhibitors(2008)36 cited
• → Identification of Novel β3-Adrenoceptor Agonists Using Energetic Analysis, Structure Based Pharmacophores and Virtual Screening(2012)4 cited