期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 3, 页码 1205-1214出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm501402x
关键词
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资金
- Australian National Health and Medical Research Council (NHMRC) [1045995, 1009785, 1022693, 1025150]
- NHMRC
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.
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