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

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)1205 - 1214
Number of pages10
JournalJournal of Medicinal Chemistry
Volume58
Issue number3
DOIs
Publication statusPublished - 2015

Cite this

@article{2833f558783647b9ad759bd65ca76e2a,
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.",
author = "Shane Devine and Mark Mulcair and Cael Debono and Leung, {Eleanor Wai Wai} and Nissink, {J Willem M} and Lim, {San Sui} and Chandrashekaran, {Indu Rajmohan} and Mansha Vazirani and Biswaranjan Mohanty and Simpson, {Jamie Scott} and Baell, {Jonathan Bayldon} and Scammells, {Peter John} and Norton, {Raymond Stanley} and Martin Scanlon",
year = "2015",
doi = "10.1021/jm501402x",
language = "English",
volume = "58",
pages = "1205 -- 1214",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "3",

}

Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold. / Devine, Shane; Mulcair, Mark; Debono, Cael; Leung, Eleanor Wai Wai; Nissink, J Willem M; Lim, San Sui; Chandrashekaran, Indu Rajmohan; Vazirani, Mansha; Mohanty, Biswaranjan; Simpson, Jamie Scott; Baell, Jonathan Bayldon; Scammells, Peter John; Norton, Raymond Stanley; Scanlon, Martin.

In: Journal of Medicinal Chemistry, Vol. 58, No. 3, 2015, p. 1205 - 1214.

Research output: Contribution to journalArticleResearchpeer-review

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.

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U2 - 10.1021/jm501402x

DO - 10.1021/jm501402x

M3 - Article

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EP - 1214

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

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