期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 3, 页码 1080-1085出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.11.102
关键词
DNA-encoded library; Peptide nucleic acid (PNA); Fragment based drug discovery; PTP1B
资金
- Swiss National Science Foundation
- NCCR in Chemical Biology
- ERC grant [ERC 201749]
DNA display of PNA-encoded libraries was used to pair fragments containing different phosphotyrosine surrogates with diverse triazoles. Microarray-based screening of the combinatorially paired fragment sets (62,500 combinations) against a prototypical phosphatase, PTP1B, was used to identify the fittest fragments. A focused library (10,000 members) covalently pairing identified fragments with linkers of different length and geometry was synthesized. Screening of the focused library against PTP1B and closely related TCPTP revealed orthogonal inhibitors. The selectivity of the identified inhibitors for PTP1B versus TCPT was confirmed by enzymatic inhibition assay. (C) 2015 Elsevier Ltd. All rights reserved.
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