Kinetic Target-Guided Synthesis


Fragment-based lead discovery approaches have garnered increasing attention in the last two decades. Kinetic Target-Guided Synthesis (KTGS) is a fragment-based lead discovery approach which enables the identification of promising protein inhibitors through template-mediated assembly of reactive small molecule fragments. This strategy involves the biological target participating in the irreversible assembly of its own inhibitory bidentate ligand from a pool of complementary reactive fragments. Despite being described in detail in the early 1980s, KTGS is relatively unexplored and has primarily been applied to enzymatic targets. Our group developed the first KTGS approach for the identification of compounds disrupting protein-protein interactions. These efforts demonstrated the suitability of in situ amidation reactions between thioacids and sulfonyl azides, known as sulfo-click reactions, for KTGS experiments involved in targeting Bcl-xL – a key regulator of cellular apoptosis.


Our group is currently involved in efforts to optimize key features of KTGS - such as preparation of fragments and methods of hit detection. This pursuit led to the development of an improved second-generation strategy which allows for easier preparation of fragments, increased throughput, and more precise analysis of generated data. Our second generation KTGS strategy was successfully executed with an expanded fragment library to target proteins implicated in infectious diseases. We aim to continue optimizing KTGS with the goal of designing a simple, rapid, and precise fragment-based lead discovery technique that may contribute to addressing some of the most challenging and deadly diseases in the developing world.

Selected Publications on Kinetic Target-Guided Synthesis:


Sulfo-click reaction via in situ generated thioacids and its application in kinetic target-guided synthesis.

Namelikonda, N. K.; Manetsch, R. Chem. Commun. (Camb). 2012, 48, 1526–1528.


Screening of protein-protein interaction modulators via sulfo-click kinetic target-guided synthesis. 

Kulkarni, S. S.; Hu, X.; Doi, K.; Wang, H.-G.; Manetsch, R. ACS Chem. Biol. 2011, 6, 724–732.