Beyond Affinity: Enthalpy鈥揈ntropy Factorization Unravels Complexity of a Flat Structure鈥揂ctivity Relationship for Inhibition of a tRNA-Modifying Enzyme

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• 作者：Manuel Neeb ; Michael Betz ; Andreas Heine ; Luzi Jakob Barandun ; Christoph Hohn ; Fran莽ois Diederich ; Gerhard Klebe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 10, 2014
• 年：2014
• 卷：57
• 期：13
• 页码：5566-5578
• 全文大小：638K
• ISSN：1520-4804

文摘

Lead optimization focuses on binding-affinity improvement. If a flat structure鈥揳ctivity relationship is detected, usually optimization strategies are abolished as unattractive. Nonetheless, as affinity is composed of an enthalpic and entropic contribution, factorization of both can unravel the complexity of a flat, on first sight tedious SAR. In such cases, the binding free energy of different ligands can be rather similar, but it can factorize into enthalpy and entropy distinctly. We investigated the thermodynamic signature of two classes of lin-benzopurines binding to tRNA鈭抔uanine transglycosylase. While the differences are hardly visible in the free energy, they involve striking enthalpic and entropic changes. Analyzing thermodynamics along with structural features revealed that one ligand set binds to the protein without inducing significant changes compared to the apo structure; however, the second series provokes complex adaptation, leading to a conformation similar to the substrate-bound state. In the latter state, a cross-talk between two pockets is suggested.