Compared to inhibitors, which constitute the vast majority of today's drugs, enzyme activators have considerable advantages, especially in the context of enzymes that regulate reactive flux through metabolic pathways associated with chronic, age-related diseases and lifespan. Across all families of enzymes, only a dozen or so distinct classes of small molecule activators have been characterized. Enzyme activators that are not based on naturally evolved allosteric mechanisms are much more difficult to design than inhibitors, because enzymatic catalysis has been optimized over billions of years of evolution. Here, we introduce modes of enzyme activation based on the catalytic reaction mechanisms of enzymes for which naturally evolved activators may not exist. We establish biophysical properties of small molecule modulators that are necessary to achieve desired changes in the steady state and non-steady state parameters of these enzymes, including changes in local conformational degrees of freedom conducive to the enhancement of catalytic activity that can be identified through computational modeling of their active sites. We illustrate how the modes of action of several compounds reported to activate enzymes without allosteric sites may be understood using the framework presented. We also present simulations and new experimental results in support of this framework, including identification of the mechanism of the compound honokiol that activates the human SIRT3 enzyme, which does not contain an allosteric site, under physiologically relevant conditions.

中文翻译：

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基于机理的酶激活化合物

与构成当今大多数药物的抑制剂相比，酶激活剂具有相当大的优势，尤其是在通过与慢性，与年龄相关的疾病和寿命相关的代谢途径调节反应通量的酶的背景下。在所有酶家族中，只有十几种左右的小分子活化剂被表征。与抑制剂相比，不基于自然进化的变构机制的酶激活剂的设计难度要大得多，因为数十亿年的进化已优化了酶催化作用。在这里，我们基于可能不存在自然进化的活化剂的酶的催化反应机理，介绍酶的活化方式。我们建立了小分子调节剂的生物物理特性，这些特性对于实现这些酶的稳态和非稳态参数的所需变化是必需的，包括有助于提高催化活性的局部构象自由度的变化，可以通过计算确定对其活动站点进行建模。我们举例说明了如何使用提出的框架来理解报道的几种化合物激活没有变构位点的酶的作用方式。我们还提供了支持这一框架的模拟和新的实验结果，包括在生理相关条件下鉴定激活人类SIRT3酶的复合厚朴酚的机制，该酶不含变构位点。