Design and evaluation of a novel class-directed 2D fingerprint to search for structurally diverse active compounds

Recent attempts to increase similarity search performance using molecular fingerprints have mostly focused on the evaluation of alternative similarity metrics or scoring schemes, rather than the development of new types of fingerprints. Here, we introduce a novel 2D fingerprint design (property descriptor value range-derived fingerprint or PDR-FP) that involves activity-oriented selection of property descriptors and the transformation of descriptor value ranges into a binary format such that each fingerprint bit position represents a specific value interval. The design is tailored toward multiple-template similarity searching and permits training on specific activity classes. In search calculations on 15 compound classes of increasing structural diversity, the PDR fingerprint performed better than other state-of-the-art 2D fingerprints. Among the structurally diverse classes were six compound sets with peptide character, which represent a notoriously difficult chemotype for 2D similarity searching. In these cases, PDR-FP produced promising results, whereas other fingerprint methods mostly failed. PDR-FP is specifically designed for search calculations on structurally diverse compounds, and these calculations are not influenced by molecular size effects, which represent a general problem for similarity searching using bit string representations.