Title | ||
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Novel Scaffold Fingerprint (SFP): Applications in Scaffold Hopping and Scaffold-Based Selection of Diverse Compounds. |
Abstract | ||
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A novel 2D Scaffold FingerPrint (SFP) for mining ring fragments is presented. The rings are described not only by their topology, shape, and pharmacophoric features (hydrogen-bond acceptors and donors, their relative locations, sp3 carbons, and chirality) but also by the position and nature of their growing vectors because they play a critical role from the drug discovery perspective. SFP can be used (i) to identify alternative chemotypes to a reference ring either in a visual mode or by running quantitative similarity searches and (ii) in chemotype-based diversity selections. Two retrospective case studies focused on melanin concentrating hormone 1-receptor antagonists (MCH-R1) and phosphodiesterase-5 inhibitors (PDE5) demonstrate the capability of this method for identifying novel structurally different and synthetically accessible chemotypes. Good enrichment factor (155 and 219) and recall values (46% and 73%) are found within the first 100 ranked hits (0.3% of screened database). Our 2D SFP descriptor outperforms well-validated current gold-standard 2D fingerprints (ECFP_6) and 3D approaches based on shape and electrostatic similarity. Scaffold-based selection of diverse compounds has a critical impact on corporate library design and compound acquisitions; thus, a novel strategy is introduced that uses diverse scaffold selections using this SFP descriptor combined with R-group selection at the different substitution sites. Both approaches are available as part of an interactive web-based application that requires minimal input and no computational knowledge by medicinal chemists. |
Year | DOI | Venue |
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2015 | 10.1021/ci500542e | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
DocType | Volume | Issue |
Journal | 55 | 1 |
ISSN | Citations | PageRank |
1549-9596 | 2 | 0.37 |
References | Authors | |
0 | 3 |
Name | Order | Citations | PageRank |
---|---|---|---|
Obdulia Rabal | 1 | 162 | 8.61 |
Fares Ibrahim Amr | 2 | 2 | 0.37 |
Julen Oyarzabal | 3 | 60 | 4.85 |