TY - JOUR
T1 - Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold
AU - Devine, Shane
AU - Mulcair, Mark
AU - Debono, Cael
AU - Leung, Eleanor Wai Wai
AU - Nissink, J Willem M
AU - Lim, San Sui
AU - Chandrashekaran, Indu Rajmohan
AU - Vazirani, Mansha
AU - Mohanty, Biswaranjan
AU - Simpson, Jamie Scott
AU - Baell, Jonathan Bayldon
AU - Scammells, Peter John
AU - Norton, Raymond Stanley
AU - Scanlon, Martin
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://pubs.acs.org/doi/pdf/10.1021/jm501402x
U2 - 10.1021/jm501402x
DO - 10.1021/jm501402x
M3 - Article
VL - 58
SP - 1205
EP - 1214
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -