Biophysical and physicochemical methods differentiate highly ligand-efficient human D-amino acid oxidase inhibitors
Biophysical and physicochemical methods differentiate highly ligand-efficient human D-amino acid oxidase inhibitors
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DOI：
10.1016/j.ejmech.2011.04.023
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发表时间：
2011-10-01
影响因子：
6.7
通讯作者：
Kruse, Chris G.
中科院分区：
文献类型：
--
作者：
Lange, Jos H. M.;Venhorst, Jennifer;Kruse, Chris G.
许多早期的药物研究工作过于简化，从而不能提供关键参数，如靶配体结合的动力学和热力学。应用一组人D-氨基酸氧化酶（DAAO）抑制剂1-6，以证明关键生物物理技术和物理化学方法在区分化学实体中的影响，这些化学实体无法根据其标准化效价（配体效率）值充分区分。所得生物物理和理化数据与相关药效学和药代动力学特性相关。基于观察到的k（off）值，表面等离子体共振数据表明与1-4相比，5和6的靶配体停留时间延长。1-6与DAAO酶的等温滴定量热法衍生的热力学结合曲线显示Δ H和Δ S对其Δ G值的有利贡献。令人惊讶的是，与结构上密切相关的稠合双环酸4相比，3的热力学结合特征引起了Delta H对Delta的显著更高的有利贡献。分子动力学模拟和自由能计算的1，3，和4导致新的见解结合过程中的热力学性质在原子水平上，并在不同的热力学签名3和4。所提出的整体方法预计将有助于在早期研究阶段确定具有最佳性能的化合物。(C)2011年Elsevier Masson SAS。All rights reserved.
Many early drug research efforts are too reductionist thereby not delivering key parameters such as kinetics and thermodynamics of target ligand binding. A set of human D-Amino Acid Oxidase (DAAO) inhibitors 1-6 was applied to demonstrate the impact of key biophysical techniques and physicochemical methods in the differentiation of chemical entities that cannot be adequately distinguished on the basis of their normalized potency (ligand efficiency) values. The resulting biophysical and physicochemical data were related to relevant pharmacodynamic and pharmacokinetic properties. Surface Plasmon Resonance data indicated prolonged target ligand residence times for 5 and 6 as compared to 1-4, based on the observed k(off) values. The Isothermal Titration Calorimetry-derived thermodynamic binding profiles of 1-6 to the DAAO enzyme revealed favorable contributions of both Delta H and Delta S to their Delta G values. Surprisingly, the thermodynamic binding profile of 3 elicited a substantially higher favorable contribution of Delta H to Delta in comparison with the structurally closely related fused bicyclic acid 4. Molecular dynamics simulations and free energy calculations of 1, 3, and 4 led to novel insights into the thermodynamic properties of the binding process at an atomic level and in the different thermodynamic signatures of 3 and 4. The presented holistic approach is anticipated to facilitate the identification of compounds with best-in-class properties at an early research stage. (C) 2011 Elsevier Masson SAS. All rights reserved.