Devine Shane M, Mulcair Mark D, Debono Cael O, Leung Eleanor W W, Nissink J Willem M, Lim San Sui, Chandrashekaran Indu R, Vazirani Mansha, Mohanty Biswaranjan, Simpson Jamie S, Baell Jonathan B, Scammells Peter J, Norton Raymond S, Scanlon Martin J
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
J Med Chem. 2015 Feb 12;58(3):1205-14. doi: 10.1021/jm501402x. Epub 2015 Jan 16.
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.
我们已鉴定出一类被称为2-氨基噻唑（2-ATs）的分子，它们是生物物理结合试验中频繁出现的片段。4-苯基噻唑-2-胺在针对多种蛋白质靶点的14次筛选中均被鉴定为活性片段，这说明了这一点，表明该骨架对于基于片段的药物发现而言并非一个好的起始点。这促使我们在用于基于片段的药物发现（FBDD）的学术片段库以及用于高通量筛选（HTS）的两个更大的化合物库的背景下分析该骨架。该分析表明，此类“混杂的2-氨基噻唑”（PrATs）在FBDD和HTS环境下均表现为频繁出现的活性片段，尽管在基于片段的研究中该问题更为突出。由于2-ATs存在于已知药物中，它们不一定被视为不良分子，但鉴于其混杂性以及将它们优化为先导化合物所面临的困难，我们认为它们对于片段库而言并非好的骨架。
