Scaffold-Hopping: How Far Can You Jump?

• Published in: QSAR & combinatorial science Vol. 25; no. 12; pp. 1162 - 1171
• Main Authors: Schneider, Gisbert, Schneider, Petra, Renner, Steffen
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.12.2006; WILEY‐VCH Verlag
• Subjects: Chemotype; Drug design; Molecular diversity; Similarity searching; Virtual screening
• ISSN: 1611-020X; 1611-0218
• DOI: 10.1002/qsar.200610091

Finding new isofunctional chemotypes with the aim of identifying new lead candidates remains a challenging task in medicinal chemistry. Different virtual screening techniques have been shown to be useful for this scaffold‐hopping process. We have compiled recent examples of scaffold‐hops that were achieved by virtual screening. Most of these techniques rely on some sort of similarity estimation between known reference molecules and screening compounds, some include receptor‐structure information and scoring of the ligand–receptor interaction. In this review, we discuss current scaffold‐hopping strategies and pinpoint potential future directions. Challenges for future research lie in the identification of an appropriate level of ion from an atomistic molecule representation to allow for the detection of isofunctional chemotypes, the rational design of chemotype diversity in screening libraries, and an understanding of the distribution of similarity scores for a given screening library.