title: Charting Biologically Relevant Spirocyclic Compound Space.
abstract: Spirocycles frequently occur in natural products and experience increasing interest in drug discovery, given their richness in sp3centers and distinct three-dimensionality. We have systematically explored chemical space populated with currently available bioactive spirocycles. Compounds containing spiro systems were classified and their scaffolds and spirocyclic ring combinations analyzed. Nearly 47 000 compounds were identified that contained spirocycles in different structural contexts and were active against roughly 200 targets, among which several pharmaceutically relevant members of the G protein-coupled receptor (GPCR) family were identified. Spirocycles and corresponding compounds displayed notable scaffold diversity but contained only limited numbers of combinations of differently sized rings. These observations indicate that there should be significant potential to further expand spirocyclic chemical space for drug discovery, exploiting the privileged substructure concept. Inspired by those findings, we embarked on the design and chemical synthesis of three distinct novel spirocyclic scaffolds that qualify for downstream library synthesis, thus exploring principally new chemical space with high potential for pharmaceutical research.
authors.affiliation: Mercachem, Kerkenbos 1013, 6546 BB Nijmegen, P.O. Box 6747, 6503 GE, Nijmegen, The Netherlands.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller
authors.affiliation: Mercachem, Kerkenbos 1013, 6546 BB Nijmegen, P.O. Box 6747, 6503 GE, Nijmegen, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Berkenbosch
authors.affiliation: Mercachem, Kerkenbos 1013, 6546 BB Nijmegen, P.O. Box 6747, 6503 GE, Nijmegen, The Netherlands.
authors.forename: Jorg C J
authors.initials: JC
authors.lastname: Benningshof
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, 53113, Bonn, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stumpfe
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, 53113, Bonn, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry; D062126:Databases, Chemical; D055808:Drug Discovery; D008968:Molecular Conformation; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D001688:Biological Products; D043562:Receptors, G-Protein-Coupled; D013141:Spiro Compounds; D010447:Peptide Hydrolases
keywords: compound distribution; computational analysis; scaffold synthesis; spiro compounds; structural biology