5 research outputs found
Target binding molecules identified by kinetic target-guided synthesis
Methods of identifying target binding molecules by target guided synthesis are provided. The methods include providing two or more fragments capable of reacting to form the target binding molecule and mixing the fragments with the target. The methods can be used to identify target binding molecules that bind targets such as proteins or nucleic acids, including those that bind shallow binding pockets on the surface of such targets. The methods are applied to the Bcl-XL and Mcl-1 proteins from the Bcl-2 family of proteins. Using thio acid and sulfonyl azide fragments capable of reacting through sulfo-click chemistry, new acyl sulfonamides are identified that bind one or both of the Bcl-XL and Mcl-1 proteins. Pharmaceutical formulations of these target binding molecules are also provided
Going beyond Binary: Rapid Identification of Protein–Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach
Kinetic target-guided synthesis (KTGS) is a powerful
screening
approach that enables identification of small molecule modulators
for biomolecules. While many KTGS variants have emerged, a majority
of the examples suffer from limited throughput and a poor signal/noise
ratio, hampering reliable hit detection. Herein, we present our optimized
multifragment KTGS screening strategy that tackles these limitations.
This approach utilizes selected reaction monitoring liquid chromatography
tandem mass spectrometry for hit detection, enabling the incubation
of 190 fragment combinations per screening well. Consequentially,
our fragment library was expanded from 81 possible combinations to
1710, representing the largest KTGS screening library assembled to
date. The expanded library was screened against Mcl-1, leading to
the discovery of 24 inhibitors. This work unveils the true potential
of KTGS with respect to the rapid and reliable identification of hits,
further highlighting its utility as a complement to the existing repertoire
of screening methods used in drug discovery
Going beyond Binary: Rapid Identification of Protein–Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach
Kinetic target-guided synthesis (KTGS) is a powerful
screening
approach that enables identification of small molecule modulators
for biomolecules. While many KTGS variants have emerged, a majority
of the examples suffer from limited throughput and a poor signal/noise
ratio, hampering reliable hit detection. Herein, we present our optimized
multifragment KTGS screening strategy that tackles these limitations.
This approach utilizes selected reaction monitoring liquid chromatography
tandem mass spectrometry for hit detection, enabling the incubation
of 190 fragment combinations per screening well. Consequentially,
our fragment library was expanded from 81 possible combinations to
1710, representing the largest KTGS screening library assembled to
date. The expanded library was screened against Mcl-1, leading to
the discovery of 24 inhibitors. This work unveils the true potential
of KTGS with respect to the rapid and reliable identification of hits,
further highlighting its utility as a complement to the existing repertoire
of screening methods used in drug discovery
Going beyond Binary: Rapid Identification of Protein–Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach
Kinetic target-guided synthesis (KTGS) is a powerful
screening
approach that enables identification of small molecule modulators
for biomolecules. While many KTGS variants have emerged, a majority
of the examples suffer from limited throughput and a poor signal/noise
ratio, hampering reliable hit detection. Herein, we present our optimized
multifragment KTGS screening strategy that tackles these limitations.
This approach utilizes selected reaction monitoring liquid chromatography
tandem mass spectrometry for hit detection, enabling the incubation
of 190 fragment combinations per screening well. Consequentially,
our fragment library was expanded from 81 possible combinations to
1710, representing the largest KTGS screening library assembled to
date. The expanded library was screened against Mcl-1, leading to
the discovery of 24 inhibitors. This work unveils the true potential
of KTGS with respect to the rapid and reliable identification of hits,
further highlighting its utility as a complement to the existing repertoire
of screening methods used in drug discovery
Going beyond Binary: Rapid Identification of Protein–Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach
Kinetic target-guided synthesis (KTGS) is a powerful
screening
approach that enables identification of small molecule modulators
for biomolecules. While many KTGS variants have emerged, a majority
of the examples suffer from limited throughput and a poor signal/noise
ratio, hampering reliable hit detection. Herein, we present our optimized
multifragment KTGS screening strategy that tackles these limitations.
This approach utilizes selected reaction monitoring liquid chromatography
tandem mass spectrometry for hit detection, enabling the incubation
of 190 fragment combinations per screening well. Consequentially,
our fragment library was expanded from 81 possible combinations to
1710, representing the largest KTGS screening library assembled to
date. The expanded library was screened against Mcl-1, leading to
the discovery of 24 inhibitors. This work unveils the true potential
of KTGS with respect to the rapid and reliable identification of hits,
further highlighting its utility as a complement to the existing repertoire
of screening methods used in drug discovery