How much binding affinity can be gained by filling a cavity?
How much binding affinity can be gained by filling a cavity?
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DOI：
10.1111/j.1747-0285.2009.00921.x
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发表时间：
2010-02
影响因子：
3
通讯作者：
Freire E
中科院分区：
文献类型：
--
作者：
Kawasaki Y;Chufan EE;Lafont V;Hidaka K;Kiso Y;Mario Amzel L;Freire E
结合亲和力优化在药物开发过程中至关重要。在这里，我们评估的热力学后果填充的结合腔的功能性增加的货车范德华半径（-H，-F，-Cl和CH 3），提高几何拟合，而不参与氢键或其他特定的相互作用。我们观察到两个数量级的结合亲和力增加。这一过程似乎分为三个阶段。第一阶段与稳定的货车范德华相互作用的形成有关。该阶段的特征在于结合焓的增加和结合熵的损失，这归因于构象自由度的损失。对于本文中提出的特定情况，焓增益为−1.5 kcal/mol，而熵损失为+0.9 kcal/mol，导致净亲和力增益为3.5倍。第二阶段的特点是同时的双折射和熵增益。该阶段将结合亲和力提高了25倍。第三阶段代表趋势的崩溃，并由引入大于结合腔本身的化学官能团（CH（CH 3）2）引发。它的特点是焓和亲和力损失大。与每个阶段相关联的热力学特征为铅优化提供了指导方针。
Binding affinity optimization is critical during drug development. Here we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (-H, -F, -Cl and CH3) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this paper, the enthalpy gain amounts to −1.5 kcal/mol while the entropic losses amount to +0.9 kcal/mol resulting in a net 3.5-fold affinity gain. The second phase is characterized by simultaneous enthalpic and entropic gains. This phase improves the binding affinity 25-fold. The third phase represents the collapse of the trend and is triggered by the introduction of chemical functionalities larger than the binding cavity itself (CH(CH3)2). It is characterized by large enthalpy and affinity losses. The thermodynamic signatures associated with each phase provide guidelines for lead optimization.
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影响因子：
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