Small Molecule NS11021 Promotes BK Channel Activation by Increasing Inner Pore Hydration,Journal of Chemical Information and Modeling

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Small Molecule NS11021 Promotes BK Channel Activation by Increasing Inner Pore Hydration
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-09-12 , DOI: 10.1021/acs.jcim.4c01012
Erik B Nordquist ₁ , Zhiguang Jia ₁ , Jianhan Chen ₁

Affiliation

The Ca²⁺ and voltage-gated big potassium (BK) channels are implicated in various diseases, including heart disease, asthma, epilepsy, and cancer, but remain an elusive drug target. A class of negatively charged activators (NCAs) have been demonstrated to promote the activation of several potassium channels including BK channels by binding to the hydrophobic inner pore, yet the underlying molecular mechanism of action remains poorly understood. In this work, we analyze the binding mode and potential activation mechanism of a specific NCA named NS11021 using atomistic simulations. The results show that NS11021 binding to the pore in deactivated BK channels is nonspecific and dynamic. The binding free energy of −8.3 ± 0.7 kcal/mol (K_D = 0.3–3.1 μM) calculated using umbrella sampling agrees quantitatively with the experimental EC50 range of 0.4–2.1 μM. The bound NS11021 remains dynamic and is distal from the filter to significantly impact its conformation. Instead, NS11021 binding significantly enhances the pore hydration due to the charged tetrazol-phenyl group, thereby promoting the opening of the hydrophobic gate. We further show that the free energy barrier to K⁺ permeation is reduced by ∼3 kcal/mol regardless of the binding pose, which could explain the ∼62-fold increase in the intrinsic opening of BK channels measured experimentally. Taken together, these results support the idea that the molecular mechanism of NS11021 derives from increasing the hydration level of the conformationally closed pore, which does not depend on specific binding and likely explains the ability of NCAs to activate multiple K⁺ channels.

中文翻译：

小分子 NS11021 通过增加毛孔内部水合作用来促进 BK 通道激活

Ca²⁺ 和电压门控大钾（BK）通道与各种疾病有关，包括心脏病、哮喘、癫痫和癌症，但仍然是一个难以捉摸的药物靶点。一类带负电荷的激活剂（NCA）已被证明通过与疏水内孔结合来促进包括 BK 通道在内的多个钾通道的激活，但潜在的分子作用机制仍然知之甚少。在这项工作中，我们使用原子模拟分析了名为 NS11021 的特定 NCA 的结合模式和潜在激活机制。结果表明，NS11021 与失活 BK 通道中孔的结合是非特异性和动态的。使用伞式采样计算的结合自由能为 −8.3 ± 0.7 kcal/mol （K_D = 0.3–3.1 μM），定量上与 0.4–2.1 μM 的实验 EC50 范围一致。结合NS11021保持动态，并且远离过滤器，从而显着影响其构象。相反，由于带电的四唑-苯基，NS11021结合显着增强了孔水合作用，从而促进了疏水门的打开。我们进一步表明，无论结合姿势如何，对 K⁺ 渗透的自由能屏障都减少了 ∼3 kcal/mol，这可以解释实验测量的 BK 通道的内在开放度增加了 ∼62 倍。综上所述，这些结果支持这样的观点，即 NS11021 的分子机制源于增加构象闭合孔的水合作用水平，这不依赖于特异性结合，可能解释了 NCA 激活多个 K⁺ 通道的能力。

更新日期：2024-09-12

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