Proteome-wide prediction of targets for aspirin: new insight into the molecular mechanism of aspirin

Abstract

Besides its anti-inflammatory, analgesic and anti-pyretic properties, aspirin is used for the prevention of cardiovascular disease and various types of cancer. The multiple activities of aspirin likely involve several molecular targets and pathways rather than a single target. Therefore, systematic identification of these targets of aspirin can help us understand the underlying mechanisms of the activities. In this study, we identified 23 putative targets of aspirin in the human proteome by using binding pocket similarity detecting tool combination with molecular docking, free energy calculation and pathway analysis. These targets have diverse folds and are derived from different protein family. However, they have similar aspirin-binding pockets. The binding free energy with aspirin for newly identified targets is comparable to that for the primary targets. Pathway analysis revealed that the targets were enriched in several pathways such as vascular endothelial growth factor (VEGF) signaling, Fc epsilon RI signaling and arachidonic acid metabolism, which are strongly involved in inflammation, cardiovascular disease and cancer. Therefore, the predicted target profile of aspirin suggests a new explanation for the disease prevention ability of aspirin. Our findings provide a new insight of aspirin and its efficacy of disease prevention in a systematic and global view.

Keywords: Aspirin; Binding site; Cancer; Cardiovascular disease; Molecular docking; Target.

Figure 1. The pipeline of the structural proteome-wide prediction of aspirin targets.

Starting with the binding sites of aspirin (BSiteAs), the pipeline integrates local structure detecting, molecular docking, free energy calculation, and pathway analysis.

Figure 2. Structural diversity of the putative targets.

(A) The structural similarity network of the putative targets and the structures of 1OXR and 1PTH are also shown. We analyzed the structural similarity of the 23 putative targets by structural alignment. The RMSD between two linked proteins in the network is smaller than 4 Å. The primary targets of aspirin are colored with green, and the newly identified targets are colored with red. (B) Structural alignment of the putative binding sites of aspirin (BSiteAs) from two proteins PLA2G1B (green) and CDK13 (red).

Figure 3. Diverse binding modes of aspirin to the putative targets.

The docking experiments reveal diverse binding modes of aspirin to these targets (A) Aspirin binding to protein CDK13 (3LQ5.pdb). (B) Aspirin binding to protein RAC1 (1RYH.pdb). © Aspirin binding to protein ITGAL (3BQM.pdb). The overview and close-up view of the binding mode of aspirin to their putative targets are shown in A-C and D-F, respectively. The close-up view (D-F) show all amino acids in the vicinity of aspirin. Aspirin and the known ligands of the three proteins are colored with green and red, respectively (A-C). The residues involved in binding to both aspirin and the ligands are shown as sticks and colored with blue (A-C). SLQ (A), GNP (B) and BQM © are ATP-analog inhibitor of the kinase CDK13, the substrate of the protein RAC1 and the inhibitor of protein ITGAL, respectively.

Figure 4. An integrated interaction network of targets-cellular effect based on their associated pathways.

Predicted targets, represented by green circles in the network, regulate VEGF, epsilon RI signaling, arachidonic acid metabolism, and MAPK pathways through direct or indirect interactions with intermediate proteins (gray circles) connecting the pathways. Red squares represent cellular effects. Black lines represent activation.