Incorporation of rapid thermodynamic data in fragment-based drug discovery.

Akihiro Kobe, Jose M M Caaveiro, Shinya Tashiro, Daisuke Kajihara, Masato Kikkawa, Tomoya Mitani, Kouhei Tsumoto

Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.

Journal of medicinal chemistry 2013 Mar 14

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Fragment-based drug discovery (FBDD) has enjoyed increasing popularity in recent years. We introduce SITE (single-injection thermal extinction), a novel thermodynamic methodology that selects high-quality hits early in FBDD. SITE is a fast calorimetric competitive assay suitable for automation that captures the essence of isothermal titration calorimetry but using significantly fewer resources. We describe the principles of SITE and identify a novel family of fragment inhibitors of the enzyme ketosteroid isomerase displaying high values of enthalpic efficiency.

Citation

Akihiro Kobe, Jose M M Caaveiro, Shinya Tashiro, Daisuke Kajihara, Masato Kikkawa, Tomoya Mitani, Kouhei Tsumoto. Incorporation of rapid thermodynamic data in fragment-based drug discovery. Journal of medicinal chemistry. 2013 Mar 14;56(5):2155-9