Identification of Target Associations for Polypharmacology from Analysis of Crystallographic Ligands of the Protein Data Bank

The design of a chemical entity that potently and selectively binds to a biological target of therapeutic relevance has dominated the scene of drug discovery so far. However, recent findings suggest that multitarget ligands may be endowed with superior efficacy and be less prone to drug resistance. The Protein Data Bank (PDB) provides experimentally validated structural information about targets and bound ligands. Therefore, it represents a valuable source of information to help identifying active sites, understanding pharmacophore requirements, designing novel ligands, and inferring structure-activity relationships. In this study, we performed a large-scale analysis of the PDB by integrating different ligand-based and structure-based approaches, with the aim of identifying promising target associations for polypharmacology based on reported crystal structure information. First, the 2D and 3D similarity profiles of the crystallographic ligands were evaluated using different ligand-based methods. Then, activity data of pairs of similar ligands binding to different targets were inspected by comparing structural information with bioactivity annotations reported in the ChEMBL, BindingDB, BindingMOAD, and PDBbind databases. Afterward, extensive docking screenings of ligands in the identified cross-targets were made in order to validate and refine the ligand-based results. Finally, the therapeutic relevance of the identified target combinations for polypharmacology was evaluated from comparison with information on therapeutic targets reported in the Therapeutic Target Database (TTD). The results led to the identification of several target associations with high therapeutic potential for polypharmacology.