title: Novel Scaffold FingerPrint (SFP): applications in scaffold hopping and scaffold-based selection of diverse compounds.
abstract: 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.
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra , Avda. Pio XII 55, E-31008 Pamplona, Spain.
authors.forename: Obdulia
authors.initials: O
authors.lastname: Rabal
authors.forename: Fares Ibrahim
authors.initials: FI
authors.lastname: Amr
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
mesh_terms: D019295:Computational Biology / Q000379:methods*; D062126:Databases, Chemical; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods*; D006860:Hydrogen Bonding; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000737:chemistry; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: C540748:6-(4-chlorophenyl)-3-(3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl)-3H-thieno(3,2-d)pyrimidin-4-one; C103263:MCHR1 protein, human; D058986:Phosphodiesterase 5 Inhibitors; D011744:Pyrimidinones; D017481:Receptors, Somatostatin; D013876:Thiophenes; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf