Exploring characteristic features for effective HCN1 channel inhibition using integrated analytical approaches: 3D QSAR, molecular docking, homology modelling, ADME and molecular dynamics.

IF 2.2 4区 生物学 Q3 BIOPHYSICS
Shiwani Sharma, Priyanka Rana, Vijayta Dani Chadha, Neelima Dhingra, Tanzeer Kaur
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引用次数: 0

Abstract

Neuropathic pain (NP) is characterized by hyperalgesia, allodynia, and spontaneous pain. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel involved in neuronal hyperexcitability, has emerged as an important target for the drug development of NP. HCN channels exist in four different isoforms, where HCN1 is majorly expressed in dorsal root ganglion having an imperative role in NP pathophysiology. A specific HCN1 channel inhibitor will hold the better potential to treat NP without disturbing the physiological roles of other HCN isoforms. The main objective is to identify and analyze the chemical properties of scaffolds with higher HCN1 channel specificity. The 3D-QSAR studies highlight the hydrophobic & hydrogen bond donor groups enhance specificity towards the HCN1 channel. Further, the molecular interaction of the scaffolds with the HCN1 pore was studied by generating an open-pore model of the HCN1 channel using homology modelling and then docking the molecules with it. In addition, the important residues involved in the interaction between HCN1 pore and scaffolds were also identified. Moreover, ADME predictions revealed that compounds had good oral bioavailability and solubility characteristics. Subsequently, molecular dynamics simulation studies revealed the better stability of the lead molecules A7 and A9 during interactions and ascertained them as potential drug candidates. Cumulative studies provided the important structural features for enhancing HCN1 channel-specific inhibition, paving the way to design and develop novel specific HCN1 channel inhibitors.

利用综合分析方法探索有效抑制 HCN1 通道的特征:3D QSAR、分子对接、同源建模、ADME 和分子动力学。
神经病理性疼痛(NP)以痛觉减退、异动感和自发性疼痛为特征。超极化激活的环核苷酸门控(HCN)通道参与神经元的过度兴奋,已成为 NP 药物开发的一个重要靶点。HCN 通道有四种不同的异构体,其中 HCN1 主要在背根神经节中表达,在 NP 病理生理学中起着至关重要的作用。特异性 HCN1 通道抑制剂将具有更好的治疗 NP 的潜力,同时不会干扰其他 HCN 同工酶的生理作用。研究的主要目的是鉴定和分析具有更高 HCN1 通道特异性的支架的化学特性。3D-QSAR 研究强调疏水和氢键供体基团可增强对 HCN1 通道的特异性。此外,通过同源建模生成 HCN1 通道的开孔模型,然后将分子与之对接,研究了支架与 HCN1 孔的分子相互作用。此外,还确定了参与 HCN1 孔道与支架之间相互作用的重要残基。此外,ADME 预测显示,化合物具有良好的口服生物利用度和溶解度特性。随后的分子动力学模拟研究表明,先导分子 A7 和 A9 在相互作用过程中具有更好的稳定性,因此被确定为潜在的候选药物。累积研究提供了增强 HCN1 通道特异性抑制作用的重要结构特征,为设计和开发新型特异性 HCN1 通道抑制剂铺平了道路。
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来源期刊
European Biophysics Journal
European Biophysics Journal 生物-生物物理
CiteScore
4.30
自引率
0.00%
发文量
43
审稿时长
6-12 weeks
期刊介绍: The journal publishes papers in the field of biophysics, which is defined as the study of biological phenomena by using physical methods and concepts. Original papers, reviews and Biophysics letters are published. The primary goal of this journal is to advance the understanding of biological structure and function by application of the principles of physical science, and by presenting the work in a biophysical context. Papers employing a distinctively biophysical approach at all levels of biological organisation will be considered, as will both experimental and theoretical studies. The criteria for acceptance are scientific content, originality and relevance to biological systems of current interest and importance. Principal areas of interest include: - Structure and dynamics of biological macromolecules - Membrane biophysics and ion channels - Cell biophysics and organisation - Macromolecular assemblies - Biophysical methods and instrumentation - Advanced microscopics - System dynamics.
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