title: A 3D similarity method for scaffold hopping from known drugs or natural ligands to new chemotypes.
abstract: A primary goal of 3D similarity searching is to find compounds with similar bioactivity to a reference ligand but with different chemotypes, i.e., "scaffold hopping". However, an adequate description of chemical structures in 3D conformational space is difficult due to the high-dimensionality of the problem. We present an automated method that simplifies flexible 3D chemical descriptions in which clustering techniques traditionally used in data mining are exploited to create "fuzzy" molecular representations called FEPOPS (feature point pharmacophores). The representations can be used for flexible 3D similarity searching given one or more active compounds without a priori knowledge of bioactive conformations or pharmacophores. We demonstrate that similarity searching with FEPOPS significantly enriches for actives taken from in-house high-throughput screening datasets and from MDDR activity classes COX-2, 5-HT3A, and HIV-RT, while also scaffold or ring-system hopping to new chemical frameworks. Further, inhibitors of target proteins (dopamine 2 and retinoic acid receptor) are recalled by FEPOPS by scaffold hopping from their associated endogenous ligands (dopamine and retinoic acid). Importantly, the method excels in comparison to commonly used 2D similarity methods (DAYLIGHT, MACCS, Pipeline Pilot fingerprints) and a commercial 3D method (Pharmacophore Distance Triplets) at finding novel scaffold classes given a single query molecule.
authors.affiliation: Lead Discovery Center, Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts 02139, USA. jeremy.jenkins@pharma.novartis.com
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Jenkins
authors.forename: Meir
authors.initials: M
authors.lastname: Glick
authors.forename: John W
authors.initials: JW
authors.lastname: Davies
mesh_terms: D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry; D065127:Dopamine D2 Receptor Antagonists; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008024:Ligands; D008968:Molecular Conformation; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000737:chemistry; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D065127:Dopamine D2 Receptor Antagonists; D007527:Isoenzymes; D008024:Ligands; D017448:Receptors, Dopamine D2; D018168:Receptors, Retinoic Acid; D044406:Receptors, Serotonin, 5-HT3; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D054303:HIV Reverse Transcriptase