Discovery of Bile Acid Derivatives as Potent ACE2 Activators by Virtual Screening and Essential Dynamics

The angiotensin-converting
enzyme II (ACE2) is a key molecular
player in the regulation of vessel contraction, inflammation, and
reduction of oxidative stress. In addition, ACE2 has assumed a prominent
role in the fight against the COVID-19 pandemic-causing virus SARS-CoV-2,
as it is the very first receptor in the host of the viral spike protein.
The binding of the spike protein to ACE2 triggers a cascade of events
that eventually leads the virus to enter the host cell and initiate
its life cycle. At the same time, SARS-CoV-2 infection downregulates
ACE2 expression especially in the lung, altering the biochemical signals
regulated by the enzyme and contributing to the poor clinical prognosis
characterizing the late stage of the COVID-19 disease. Despite its
important biological role, a very limited number of ACE2 activators
are known. Here, using a combined in silico and experimental approach,
we show that ursodeoxycholic acid (UDCA) derivatives work as ACE2
activators. In detail, we have identified two potent ACE2 ligands,
BAR107 and BAR708, through a docking virtual screening campaign and
elucidated their mechanism of action from essential dynamics of the
enzyme observed during microsecond molecular dynamics calculations.
The in silico results were confirmed by in
vitro pharmacological assays with the newly identified compounds
showing ACE2 activity comparable to that of DIZE, the most potent
ACE2 activator known so far. Our work provides structural insight
into ACE2/ligand-binding interaction useful for the design of compounds
with therapeutic potential against SARS-CoV-2 infection, inflammation,
and other ACE2-related diseases.

血管紧张素转换酶II（ACE2）在血管收缩、炎症调节及氧化应激减轻的调控过程中扮演着关键角色。此外，ACE2在抗击由SARS-CoV-2病毒引起的COVID-19大流行中也发挥了显著作用，因其是病毒刺突蛋白在宿主体内的首要受体。刺突蛋白与ACE2的结合引发一系列事件，最终导致病毒进入宿主细胞并启动其生命周期。与此同时，SARS-CoV-2感染下调了ACE2的表达，特别是在肺部，从而改变了由该酶调控的生化信号，并加剧了COVID-19疾病晚期的不良临床预后。尽管ACE2在生物学上具有重要作用，但已知具有ACE2激活活性的化合物数量极为有限。在本研究中，我们采用结合了计算机模拟和实验的方法，揭示了熊去氧胆酸（UDCA）衍生物作为ACE2激活剂的作用。具体而言，通过对接虚拟筛选策略，我们确定了两种高效的ACE2配体，即BAR107和BAR708，并从酶在微秒级分子动力学计算中观察到的关键动力学过程中阐明了它们的活性机制。计算机模拟的结果通过体外药理学实验得到证实，新识别的化合物展现出与已知最强的ACE2激活剂DIZE相当的ACE2活性。我们的研究为ACE2/配体结合相互作用提供了结构见解，这对设计具有针对SARS-CoV-2感染、炎症及其他ACE2相关疾病治疗潜力的化合物具有重要意义。