Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold

J Med Chem. 2015 Feb 12;58(3):1205-14. doi: 10.1021/jm501402x. Epub 2015 Jan 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery
  • High-Throughput Screening Assays
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Surface Plasmon Resonance
  • Thiazoles / chemistry*

Substances

  • Thiazoles
  • 2-aminothiazole