title: Identification of new potent GPR119 agonists by combining virtual screening and combinatorial chemistry.
abstract: Virtual screening in a huge collection of virtual combinatorial libraries has led to the identification of two new structural classes of GPR119 agonists with submicromolar in vitro potencies. Herein, we describe the virtual screening process involving feature trees fragment space searches followed by a 3D postprocessing step. The in silico findings were then filtered and prioritized, and finally, combinatorial libraries of target molecules were synthesized. Furthermore the so-called "activity-anchor principle" is introduced as an element to increase the chance to generate true hits. An activity anchor is a structural element expected to provide key contributions to a certain biological activity. Application of this technique has led to the discovery of two new GPR119-agonist hit series, one of which was further optimized to progress as a novel lead class.
authors.affiliation: Research Germany/Lead Identification and Optimization Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riss, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wellenzohn
authors.forename: Uta
authors.initials: U
authors.lastname: Lessel
authors.forename: Andreas
authors.initials: A
authors.lastname: Beller
authors.forename: Timo
authors.initials: T
authors.lastname: Isambert
authors.forename: Christoph
authors.initials: C
authors.lastname: Hoenke
authors.forename: Bernd
authors.initials: B
authors.lastname: Nosse
mesh_terms: D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D057166:High-Throughput Screening Assays; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C519854:GPR119 protein, human; D007555:Isoxazoles; D010069:Oxadiazoles; D043562:Receptors, G-Protein-Coupled; D013141:Spiro Compounds; D014508:Urea