Dynamics and modulation studies of human voltage gated Kv1.5 channel
Dynamics and modulation studies of human voltage gated Kv1.5 channel
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DOI：
10.1080/07391102.2016.1144528
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Seal, Alpana
中科院分区：
文献类型：
--
作者：
Bhuyan, Rajabrata;Seal, Alpana
电压门控 Kv1.5 通道传导超快速延迟整流器电流 (IKur)，并在动作电位持续时间的复极化中发挥关键作用。它是最快速激活的通道，并且具有很少或没有失活状态。在人类心脏细胞中，这些通道在心房肌细胞中的表达比在心室中更广泛。从其定位和功能的证据来看，Kv1.5已被宣布为治疗心房颤动（AF）的选择性药物靶点。在本研究中，我们试图鉴定 Kv1.5 的快速激活特性，并利用分子建模、对接和模拟技术研究其抑制模式。发现开放构象的通道在二棕榈酰磷脂酰胆碱膜内快速稳定，而大多数二级结构元件在闭合状态构象中丢失。其超快速特性背后的明显原因可能是由于 S4-S5 连接子中的氨基酸改变；用谷氨酰胺替代赖氨酸，反之亦然。流行的已发表药物以及新发现的先导分子能够以非常相似的模式（主要通过非极性相互作用）抑制 Kv1.5，并形成紫貂复合物。发现 V512 与其他重要残基（例如 V505、I508、A509、V512、P513 和 V516）一起是相互作用的主要贡献者。此外，两种筛选的新型化合物显示出令人惊讶的更好的抑制效力，可以考虑用于抗心律失常研究的未来前景。
The voltage gated Kv1.5 channels conduct the ultrarapid delayed rectifier current (IKur) and play critical role in repolarization of action potential duration. It is the most rapidly activated channel and has very little or no inactivated states. In human cardiac cells, these channels are expressed more extensively in atrial myocytes than ventricle. From the evidences of its localization and functions, Kv1.5 has been declared a selective drug target for the treatment of atrial fibrillation (AF). In this present study, we have tried to identify the rapidly activating property of Kv1.5 and studied its mode of inhibition using molecular modeling, docking, and simulation techniques. Channel in open conformation is found to be stabilized quickly within the dipalmitoylphosphatidylcholine membrane, whereas most of the secondary structure elements were lost in closed state conformation. The obvious reason behind its ultra-rapid property is possibly due to the amino acid alteration in S4-S5 linker; the replacement of Lysine by Glutamine and vice versa. The popular published drugs as well as newly identified lead molecules were able to inhibit the Kv1.5 in a very similar pattern, mainly through the nonpolar interactions, and formed sable complexes. V512 is found as the main contributor for the interaction along with the other important residues such as V505, I508, A509, V512, P513, and V516. Furthermore, two screened novel compounds show surprisingly better inhibitory potency and can be considered for the future perspective of antiarrhythmic survey.