当前位置: X-MOL 学术Arab. J. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Pharmacoinformatics and molecular dynamic simulation studies to identify potential small-molecule inhibitors of WNK-SPAK/OSR1 signaling that mimic the RFQV motifs of WNK kinases
Arabian Journal of Chemistry ( IF 6 ) Pub Date : 2020-04-01 , DOI: 10.1016/j.arabjc.2020.02.010
Mubarak A. Alamri

Abstract The WNK-SPAK/OSR1 signaling is a complex of serine and threonine protein kinases that involves in the regulation of human blood pressure. The WNK kinases phosphorylate and activate SPAK and OSR1 kinases through the interaction of RFQV motifs of WNK kinases with the C-terminal domains of SPAK and OSR1. Upon phosphorylation, SPAK and OSR1 phosphorylate key ion co-transporters such as Na+-[K+]-2Cl− (NKCC1-2) and K+-Cl− (KCC1-4), which are essential for electrolytes balance and blood pressure regulation. Targeting the binding site of the RFQV motifs of WNK kinases on the C-terminal domain (CTD) of SPAK and OSR1 has emerged as a valuable approach to inhibit the WNK-SPAK/OSR1 signaling pathway. Herein, an effort has been intended to pinpoint non-peptidic small-molecules that could disrupt the binding of SPAK/OSR1 to WNK kinases, hence, inhibit the SPAK and OSR1 phosphorylation and activation by WNK kinases through pharmacoinformatics and molecular dynamic simulation methodologies. A sequential structure-based virtual screening of a focus protein-protein interaction chemical library composed of 11,870 compounds lead to the identification of three compounds having good lead-compound properties with respect to their predicted inhibitory constants, pharmacophore fit scores, binding affinities, ADME-T parameters, drug-likeness properties and ligand efficiency metrics. The mechanism of interaction and binding stability of these compounds to OSR1-CTD were confirmed using molecular docking and dynamic simulation studies. Hence, the identified compounds may have therapeutic potential as novel antihypertensive agents subjected to experimental validation.

中文翻译:

药物信息学和分子动力学模拟研究,以确定模拟 WNK 激酶 RFQV 基序的 WNK-SPAK/OSR1 信号传导的潜在小分子抑制剂

摘要 WNK-SPAK/OSR1 信号是丝氨酸和苏氨酸蛋白激酶的复合物,参与人体血压的调节。WNK 激酶通过 WNK 激酶的 RFQV 基序与 SPAK 和 OSR1 的 C 端域的相互作用磷酸化和激活 SPAK 和 OSR1 激酶。磷酸化后,SPAK 和 OSR1 磷酸化关键离子共转运蛋白,如 Na+-[K+]-2Cl− (NKCC1-2) 和 K+-Cl− (KCC1-4),它们对电解质平衡和血压调节至关重要。靶向 WNK 激酶的 RFQV 基序在 SPAK 和 OSR1 的 C 端域 (CTD) 上的结合位点已成为抑制 WNK-SPAK/OSR1 信号通路的一种有价值的方法。在此,旨在查明可能破坏 SPAK/OSR1 与 WNK 激酶结合的非肽类小分子的努力,因此,通过药物信息学和分子动力学模拟方法抑制 WNK 激酶的 SPAK 和 OSR1 磷酸化和激活。对由 11,870 种化合物组成的焦点蛋白质-蛋白质相互作用化学库进行的基于序列结构的虚拟筛选导致鉴定出三种化合物,这些化合物在预测抑制常数、药效团拟合评分、结合亲和力、ADME-方面具有良好的先导化合物特性T 参数、药物相似性特性和配体效率指标。使用分子对接和动态模拟研究证实了这些化合物与 OSR1-CTD 的相互作用和结合稳定性的机制。因此,鉴定的化合物可能具有治疗潜力,作为经过实验验证的新型抗高血压药物。
更新日期:2020-04-01
down
wechat
bug