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Fragment‐Based Drug Discovery at Adaptive Protein Sites
Author(s) -
Erlanson Daniel A.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a209-b
Subject(s) - pharmacophore , drug discovery , fragment (logic) , computational biology , chemistry , small molecule , tethering , target protein , identification (biology) , disulfide bond , mass spectrometry , drug , combinatorial chemistry , biochemistry , computer science , biology , microbiology and biotechnology , algorithm , gene , botany , chromatography , pharmacology
Fragment‐based drug discovery is a rapidly emerging strategy to make lead identification and optimization more efficient. Rather than identifying drug‐sized molecules from high‐throughput screens, leads are built from smaller pharmacophores, or fragments. The main challenges are finding these fragments and then expanding or linking them into high affinity molecules. We have developed Tethering to solve these problems. The technique introduces a transient disulfide bond between fragments and a protein of interest. This boosts the affinity of those fragments that bind to the protein, allowing detection of even low‐affinity fragments. Bound fragments change the mass of the target protein, so mass spectrometry provides a rapid and convenient assay. Because of its empirical nature, Tethering can identify fragments that bind to fluxional regions of proteins that are not amenable to structure‐based drug design. A next‐generation version of the technology, Tethering with Extenders, enables the identification of a second fragment that binds in proximity to the first, thus providing a way to both identify and link fragments. I will discuss how we are using these techniques to identify kinase inhibitors.