AnchorQuery: Rapid online virtual screening for small-molecule protein-protein interaction inhibitors

Abstract

AnchorQuery (http://anchorquery.csb.pitt.edu) is a web application for rational structure-based design of protein-protein interaction (PPI) inhibitors. A specialized variant of pharmacophore search is used to rapidly screen libraries consisting of more than 31 million synthesizable compounds biased by design to preferentially target PPIs. Every library compound is accessible through one-step multi-component reaction (MCR) chemistry and contains an anchor motif that is bioisosteric to an amino acid residue. The inclusion of this anchor not only biases the compounds to interact with proteins, it also enables a rapid, sublinear time pharmacophore search algorithm. AnchorQuery provides all the tools necessary for users to perform online interactive virtual screens of millions of compounds, including pharmacophore elucidation and search, and enrichment analysis. Accessibility: AnchorQuery is freely accessible at http://anchorquery.csb.pitt.edu.

Keywords: compound libraries; multicomponent reactions; pharmacophore; small-molecules; virtual screening.

Figure 1

The AnchorQuery computational workflow.

Figure 2

The AnchorQuery web‐based interface for pharmacophore search. An example query derived from the p53/MDM2 PPI is shown (PDB ID 1YCR). Three key residues of p53 (thin wireframe) are shown with the MDM2 receptor (cartoon), the pharmacophore query (spheres and yellow anchor indicator), and a matching compounds based on the van Leusen imidazole MCR from the tryptophan‐biased library (sticks). Molecular visualization is provided by JSmol.11

Figure 3

The snippet of the Query Analysis module output showing enrichment factors (EF) with statistical significance (pEF) for reactions and starting materials in the results of a search.