Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA USA.
Commun Biol. 2019 Nov 1;2:401. doi: 10.1038/s42003-019-0648-3. eCollection 2019.
Voltage-gated potassium (Kv) channel dysfunction causes a variety of inherited disorders, but developing small molecules that activate Kv channels has proven challenging. We recently discovered that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) directly activates Kv channels KCNQ3 and KCNQ5. Here, finding that inhibitory neurotransmitter glycine does not activate KCNQs, we re-engineered it in silico to introduce predicted KCNQ-opening properties, screened by in silico docking, then validated the hits in vitro. Attaching a fluorophenyl ring to glycine optimized its electrostatic potential, converting it to a low-nM affinity KCNQ channel activator. Repositioning the phenyl ring fluorine and/or adding a methylsulfonyl group increased the efficacy of the re-engineered glycines and switched their target KCNQs. Combining KCNQ2- and KCNQ3-specific glycine derivatives synergistically potentiated KCNQ2/3 activation by exploiting heteromeric channel composition. Thus, in silico optimization and docking, combined with functional screening of only three compounds, facilitated re-engineering of glycine to develop several potent KCNQ activators.
电压门控钾 (Kv) 通道功能障碍会导致多种遗传性疾病，但开发能激活 Kv 通道的小分子一直具有挑战性。我们最近发现，抑制性神经递质γ-氨基丁酸 (GABA) 可直接激活 Kv 通道 KCNQ3 和 KCNQ5。在这里，我们发现抑制性神经递质甘氨酸不能激活 KCNQs，于是在计算机上对其进行了重新设计，引入了预测的 KCNQ 开放特性，通过计算机对接进行筛选，然后在体外验证了命中结果。将一个氟苯环连接到甘氨酸上，优化了其静电势，将其转化为低纳摩尔亲和力的 KCNQ 通道激活剂。重新设计的甘氨酸中，将苯环上的氟原子重定位和/或添加甲基磺酰基基团，可提高其效力，并改变其靶标 KCNQs。将 KCNQ2 和 KCNQ3 特异性甘氨酸衍生物组合使用，可以利用异源二聚体通道组成来协同增强 KCNQ2/3 的激活作用。因此，通过计算机优化和对接，结合仅对三种化合物进行功能筛选，有助于对甘氨酸进行重新设计，开发出几种有效的 KCNQ 激活剂。
