Interacting with GPCRs: Using Interaction Fingerprints for Virtual Screening

The expanding number of crystal structures of G protein-coupled receptors (GPCRs) has increased the knowledge on receptor function and their ability to recognize ligands. Although structure-based virtual screening has been quite successful on GPCRs, scores obtained by docking are typically not indicative for ligand affinity. Methods capturing interactions between protein and ligand in a more explicit manner, such as interaction fingerprints (IFPs), have been applied as an addition or alternative to docking. Originally IFPs captured the interactions of amino acid residues with ligands with specific definitions for the various interaction types. More complex IFPs now capture atom–atom interactions, such as in SYBYL, or fragment–fragment co-occurrences such as in SPLIF. Overall, most of the IFPs have been studied in comparison with docking in retrospective studies. For GPCRs it remains unclear which IFP should be used, if at all, and in what manner. Thus, the performance between five different IFPs was compared on five different representative GPCRs, including several extensions of the original implementations,. Results show that the more detailed IFPs, SYBYL and SPLIF, perform better than the other IFPs (Deng, Credo, and Elements). SPLIF was further tuned based on the number of poses, fingerprint similarity coefficient, and using an ensemble of structures. Enrichments were obtained that were significantly higher than initial enrichments and those obtained by 2D-similarity. With the increase in available crystal structures for GPCRs, and given that IFPs such as SPLIF enhance enrichment in virtual screens, it is anticipated that IFPs will be used in conjunction with docking, especially for GPCRs with a large binding pocket.