ja7b08366_si_004.pdb (650.45 kB)
“Inverse Drug Discovery” Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates
dataset
posted on 2017-12-21, 13:06 authored by David
E. Mortenson, Gabriel J. Brighty, Lars Plate, Grant Bare, Wentao Chen, Suhua Li, Hua Wang, Benjamin F. Cravatt, Stefano Forli, Evan T. Powers, K. Barry Sharpless, Ian A. Wilson, Jeffery W. KellyDrug candidates are generally discovered
using biochemical screens
employing an isolated target protein or by utilizing cell-based phenotypic
assays. Both noncovalent and covalent hits emerge from such endeavors.
Herein, we exemplify an “Inverse Drug Discovery” strategy
in which organic compounds of intermediate complexity harboring weak,
but activatable, electrophiles are matched with the protein(s) they
react with in cells or cell lysate. An alkyne substructure in each
candidate small molecule enables affinity chromatography–mass
spectrometry, which produces a list of proteins that each distinct
compound reacts with. A notable feature of this approach is that it
is agnostic with respect to the cellular proteins targeted. To illustrate
this strategy, we employed aryl fluorosulfates, an underexplored class
of sulfur(VI) halides, that are generally unreactive unless activated
by protein binding. Reversible aryl fluorosulfate binding, correct
juxtaposition of protein side chain functional groups, and transition-state
stabilization of the S(VI) exchange reaction all seem to be critical
for conjugate formation. The aryl fluorosulfates studied thus far
exhibit chemoselective reactivity toward Lys and, particularly, Tyr
side chains, and can be used to target nonenzymes (e.g., a hormone
carrier or a small-molecule carrier protein) as well as enzymes. The
“Inverse Drug Discovery” strategy should be particularly
attractive as a means to explore latent electrophiles not typically
used in medicinal chemistry efforts, until one reacts with a protein
target of exceptional interest. Structure–activity data can
then be used to enhance the selectivity of conjugate formation or
the covalent probe can be used as a competitor to develop noncovalent
drug candidates. Here we use the “Inverse Drug Discovery”
platform to identify and validate covalent ligands for 11 different
human proteins. In the case of one of these proteins, we have identified
and validated a small-molecule probe for the first time.