Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding

Sandner Anna; Huefner-Wulsdorf Tobias; Heine Andreas; Steinmetzer Torsten; Klebe Gerhard

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Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding

机译：晚期优化的策略：用品和盐桥屏蔽分析热力学

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Structural fixation of a ligand in its bioactive conformation may, due to entropic reasons, improve affinity. We present a congeneric series of thrombin ligands with a variety of functional groups triggering preorganization prior to binding. Fixation in solution and complex formation have been characterized by crystallography, isothermal titration calorimetry (ITC), and molecular dynamics (MD) simulations. First, we show why these preorganizing modifications do not affect the overall binding mode and how key interactions are preserved. Next, we demonstrate how preorganization thermodynamics can be largely dominated by enthalpy rather than entropy because of the significant population of low-energy conformations. Furthermore, a salt bridge is shielded by actively reducing its surface exposure, thus leading to an enhanced enthalpic binding profile. Our results suggest that the consideration of the ligand solution ensemble by MD simulation is necessary to predict preorganizing modifications that enhance the binding behavior of already promising binders.

机译：由于熵原因，改善亲和力，其生物活性构象中配体的结构固定可提高亲和力。我们呈现了一种具有各种官能团的凝血酶配体系列，在结合之前引发整个固定。通过结晶，等温滴定热量（ITC）和分子动力学（MD）模拟，表征溶液和复杂形成的固定。首先，我们展示了为什么这些预想修改不会影响整体绑定模式以及如何保留关键交互。接下来，我们证明了由于低能符合群体的显着群体，展示了预组织热力学在很大程度上是焓而不是熵的主导。此外，通过主动降低其表面暴露，盐桥被屏蔽，从而导致增强的焓结合曲线。我们的研究结果表明，MD模拟对配体溶液合并的考虑是必要的，以预测预改性改善已经有前景粘合剂的结合行为。

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《Journal of Medicinal Chemistry》 |2019年第21期|共19页
作者
Sandner Anna; Huefner-Wulsdorf Tobias; Heine Andreas; Steinmetzer Torsten; Klebe Gerhard;
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Philipps Univ Marburg Inst Pharmazeut Chem Marbacher Weg 6 D-35032 Marburg Germany;

Philipps Univ Marburg Inst Pharmazeut Chem Marbacher Weg 6 D-35032 Marburg Germany;

Philipps Univ Marburg Inst Pharmazeut Chem Marbacher Weg 6 D-35032 Marburg Germany;

Philipps Univ Marburg Inst Pharmazeut Chem Marbacher Weg 6 D-35032 Marburg Germany;

Philipps Univ Marburg Inst Pharmazeut Chem Marbacher Weg 6 D-35032 Marburg Germany;

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正文语种 eng
中图分类药学;
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1. Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding [J] . Sandner Anna, Huefner-Wulsdorf Tobias, Heine Andreas, Journal of Medicinal Chemistry . 2019,第21期

机译：晚期优化的策略：用品和盐桥屏蔽分析热力学
2. A thermodynamic model for molten salt-water solutions - Application to a thermodynamic optimization of the Ca(NO3)(2)-KNO3-H2O system [J] . Chartrand Patrice, Pelton Arthur D. The Journal of Chemical Thermodynamics . 2019,第期

机译：熔盐 - 水溶液的热力学模型 - 应用于CA的热力学优化（NO3）（2） - kno3-H2O系统
3. Friedel's salt profiles from thermogravimetric analysis and thermodynamic modelling of Portland cement-based mortars exposed to sodium chloride solution [J] . Shi Zhenguo, Geiker Mette Rica, Lothenbach Barbara, Cement & concrete composites . 2017,第期

机译：Friedel的盐曲线来自热重分析和门窗水泥基砂浆的热力学建模，暴露于氯化钠溶液
4. PRIMARY SHIELDING DESIGN FOR AN OPTIMIZED MOLTEN SALT REACTOR [C] . Zhihong ZHANG, Jianhua WANG, Xiaobin XIA, International conference on nuclear engineering . 2014

机译：优化的熔融盐反应器的初步屏蔽设计
5. Effects of dietary lysine on muscle gene expression and fatty acid profiles and on selected carcass characteristics and plasma hormone concentrations in late-stage finishing pigs. [D] . Wang, Taiji. 2016

机译：日粮赖氨酸对后期肥育猪肌肉基因表达和脂肪酸谱以及所选car体特性和血浆激素浓度的影响。
6. Thermodynamic stability of a cold-adapted protein type III antifreeze protein and energetic contribution of salt bridges [O] . Olga García-Arribas, Roberto Mateo, Melanie M. Tomczak, 2007

机译：冷适应蛋白III型抗冻蛋白的热力学稳定性以及盐桥的能量贡献
7. We develop a sequential trade model of Iceberg order execution in a limit order book. The Iceberg-trader has the freedom to expose his trading intentions or (partially) shield the true order size against other market participants. Order exposure can cause drastic market reactions (“market impact”) in the end leading to higher transaction costs. On the other hand the Iceberg trader faces a loss-in-priority when he hides his intentions, as most electronic limit order books penalize the usage of hidden liquidity. Thus the Iceberg-trader is faced with the problem to find the right trade-off. Our model provides optimal exposure strategies for Iceberg traders in limit order book markets. In particular, we provide a range of analytical statements that are in line with recent empirical findings on the determinants of trader’s exposure strategies. In this framework, we also study the market impact also market impact of limit orders. We provide optimal exposure profiles for a range of hightech stocks from the US SP500 and how they scale with the state-of-the-book. We finally test the Iceberg’s performance against the limit orders and find that Iceberg orders can significantly enhance trade performance by up to 60. [O] . Gökhan Cebiro˜glu, Ulrich Horst 100

机译：我们在限价订单簿中开发了冰山订单执行的顺序交易模型。 Iceberg-trader可以自由地揭露他的交易意图，或者（部分）屏蔽其他市场参与者的真实订单规模。订单暴露最终会导致市场反应激烈（“市场影响”），导致交易成本上升。另一方面，冰山交易员在隐藏他的意图时面临优先权损失，因为大多数电子限价订单都会惩罚隐藏流动性的使用。因此，冰山商人面临着找到正确权衡的问题。我们的模型为限额订单市场中的冰山交易者提供了最佳的风险敞口策略。特别是，我们提供了一系列分析性陈述，这些陈述与最近关于交易者暴露策略决定因素的实证研究结果一致。在此框架下，我们还研究了市场影响以及限价订单的市场影响。我们为来自美国标准普尔500指数的一系列高科技股票提供最佳曝光配置文件，以及它们如何随着本书的规模扩展。我们最终根据极限订单测试了冰山的表现，发现冰山订单可以显着提升贸易业绩高达60％。

Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding

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