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