title: Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold.
abstract: We have identified a class of molecules, known as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in biophysical binding assays. This was exemplified by 4-phenylthiazol-2-amine being identified as a hit in 14/14 screens against a diverse range of protein targets, suggesting that this scaffold is a poor starting point for fragment-based drug discovery. This prompted us to analyze this scaffold in the context of an academic fragment library used for fragment-based drug discovery (FBDD) and two larger compound libraries used for high-throughput screening (HTS). This analysis revealed that such "promiscuous 2-aminothiazoles" (PrATs) behaved as frequent hitters under both FBDD and HTS settings, although the problem was more pronounced in the fragment-based studies. As 2-ATs are present in known drugs, they cannot necessarily be deemed undesirable, but the combination of their promiscuity and difficulties associated with optimizing them into a lead compound makes them, in our opinion, poor scaffolds for fragment libraries.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: Shane M
authors.initials: SM
authors.lastname: Devine
authors.forename: Mark D
authors.initials: MD
authors.lastname: Mulcair
authors.forename: Cael O
authors.initials: CO
authors.lastname: Debono
authors.forename: Eleanor W W
authors.initials: EW
authors.lastname: Leung
authors.forename: J Willem M
authors.initials: JW
authors.lastname: Nissink
authors.forename: San Sui
authors.initials: SS
authors.lastname: Lim
authors.forename: Indu R
authors.initials: IR
authors.lastname: Chandrashekaran
authors.forename: Mansha
authors.initials: M
authors.lastname: Vazirani
authors.forename: Biswaranjan
authors.initials: B
authors.lastname: Mohanty
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Simpson
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Scanlon
mesh_terms: D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D020349:Surface Plasmon Resonance; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D013844:Thiazoles; C004483:2-aminothiazole