Bridging Structure- and Ligand-Based Virtual Screening through Fragmented Interaction Fingerprint.

Abstract

Ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS), and their combinations, are frequently conducted in modern drug discovery campaigns. As a form of combination, an amalgamation of methods from ligand- and structure-based information, termed hybrid VS approaches, has been extensively investigated such as using interaction fingerprints (IFPs) in combination with machine learning (ML) models. This approach has the potential to prioritize active compounds in terms of protein-ligand binding and ligand structural characteristics, which is assumed to be difficult using either one of the approaches. Herein, we present an IFP, named the fragmented interaction fingerprint (FIFI), for hybrid VS approaches. FIFI is constructed from the extended connectivity fingerprint atom environments of a ligand proximal to the protein residues in the binding site. Each unique ligand substructure within each amino acid residue is encoded as a bit in FIFI while retaining sequence order. From the retrospective evaluation of activity prediction using a limited number and variety of active compounds for six biological targets, FIFI consistently showed higher prediction accuracy than that using previously proposed IFPs. For the same data sets, the screening performance of LBVS, SBVS sequential VS, parallel VS, and other hybrid VS approaches was investigated. Compared to these approaches, FIFI in combination with ML showed overall stable and high prediction accuracy, except for one target: the kappa opioid receptor, where the extended connectivity fingerprint combined with ML models showed better performance than other approaches by wide margins.