Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states.
Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states.
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靶向雄激素受体无序反式激活结构域的小分子会诱导崩溃的螺旋状态的形成。
DOI：
10.1038/s41467-022-34077-z
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发表时间：
2022-10-27
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
在生理条件下不采用明确结构的内含子无序蛋白质与许多人类疾病有关。靶向雄激素受体的无序反式激活结构域的小分子已进入去势抵抗性前列腺癌（CRPC）治疗的人体试验，但没有结构或机制的理由来解释其抑制机制或相对效力。在这里，我们利用全原子分子动力学计算机模拟阐明原子详细的化合物EPI-002和EPI-7170的雄激素受体的结合机制。我们的模拟表明，这两种化合物结合在两个瞬时螺旋区域的界面处，并诱导形成部分折叠的塌缩螺旋态。我们发现EPI-7170比EPI-002更紧密地结合雄激素受体，并且我们确定了驱动更高亲和力结合的分子间相互作用网络。我们的研究结果提出了开发更有效的雄激素受体抑制剂的策略和无序蛋白质药物设计的一般策略。在这项工作中，作者报告了原子详细的计算机模拟，揭示了小分子药物与雄激素受体的内在无序区域的结合机制，雄激素受体是一种去势抵抗性前列腺癌药物靶点。
Intrinsically disordered proteins, which do not adopt well-defined structures under physiological conditions, are implicated in many human diseases. Small molecules that target the disordered transactivation domain of the androgen receptor have entered human trials for the treatment of castration-resistant prostate cancer (CRPC), but no structural or mechanistic rationale exists to explain their inhibition mechanisms or relative potencies. Here, we utilize all-atom molecular dynamics computer simulations to elucidate atomically detailed binding mechanisms of the compounds EPI-002 and EPI-7170 to the androgen receptor. Our simulations reveal that both compounds bind at the interface of two transiently helical regions and induce the formation of partially folded collapsed helical states. We find that EPI-7170 binds androgen receptor more tightly than EPI-002 and we identify a network of intermolecular interactions that drives higher affinity binding. Our results suggest strategies for developing more potent androgen receptor inhibitors and general strategies for disordered protein drug design. In this work the authors report atomically detailed computer simulations revealing the binding mechanisms of small molecule drugs to an intrinsically disordered region of the androgen receptor, a castration-resistant prostate cancer drug target.
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影响因子：
1.7
作者：
Bussi, Giovanni
通讯作者：
Bussi, Giovanni
影响因子：
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作者：
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BERENDSEN, HJC;VANDERSPOEL, D;VANDRUNEN, R
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