title: Can we discover pharmacological promiscuity early in the drug discovery process?
abstract: The term 'pharmacological promiscuity' describes the activity of a single compound against multiple targets. When undesired, promiscuity is a major safety concern that needs to be detected as early as possible in the drug discovery process. The analysis of large datasets reveals that the majority of promiscuous compounds are characterized by recognizable molecular properties and structural motifs, the most important one being a basic center with a pK(a)(B)>6. These compounds interact with a small set of targets such as aminergic GPCRs; some of these targets attract surprisingly high hit rates. In this review, we discuss current trends in the assessment of pharmacological promiscuity and propose strategies to enable early detection and mitigation.
authors.affiliation: F Hoffmann-La Roche Ltd, pRED, Pharma Research & Early Development, Discovery Chemistry, CH-4070 Basel, Switzerland. jens-uwe.peters@roche.com
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Peters
authors.forename: Jérôme
authors.initials: J
authors.lastname: Hert
authors.forename: Caterina
authors.initials: C
authors.lastname: Bissantz
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillebrecht
authors.forename: Grégori
authors.initials: G
authors.lastname: Gerebtzoff
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bendels
authors.forename: Fabien
authors.initials: F
authors.lastname: Tillier
authors.forename: Jacques
authors.initials: J
authors.lastname: Migeon
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010600:Pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations