Sharma Shiwani, Rana Priyanka, Dhingra Neelima, Kaur Tanzeer
Department of Biophysics, Panjab University, Chandigarh, India.
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Int J Appl Basic Med Res. 2025 Jul-Sep;15(3):143-151. doi: 10.4103/ijabmr.ijabmr_347_24. Epub 2025 Aug 20.
This study aims to design and develop novel lidocaine analogs specific for the Na1.7 channel using approaches.
Neuropathic pain (NP) is defined as chronic pain originating from abnormalities found within the nervous system. Voltage-gated sodium channels play a significant role in enhancing neuronal excitability, thus gained significance as a crucial target for developing drugs to treat NP. It consists of 9 different isoforms, with Na1.7 predominantly found in the dorsal root ganglion, playing a crucial role in the pathophysiology of NP. The selective inhibitors targeting the Na1.7 channel hold greater potential for treating NP while minimizing interference with the physiological functions of other sodium channel isoforms.
Atom and field-based three-dimensional (3D) quantitative structure-activity relationship (QSAR) was created using lidocaine analogs to identify the structural features required for the Na1.7 inhibitory activities. Further, the molecular interaction of the scaffold with the Na1.7 channel VSD4 was studied by docking the molecules with it followed by absorption, distribution, metabolism, and excretion (ADME) analysis.
The 3D QSAR studies revealed that the presence of hydrophobic groups and steric parameters heightened the specificity for Na1.7 channel. Docking analysis revealed that 4 compounds, i.e., A15, A14, A6, and A5, exhibited the highest binding affinity in comparison to reference drug lidocaine. Furthermore, ADME predictions indicated that the compounds exhibited favorable characteristics in terms of oral bioavailability and solubility.
This research offers valuable structural insights to improve the specific inhibition of the Na1.7 channel, facilitating the design and development of novel, Na1.7 channel-specific inhibitors.
本研究旨在采用相关方法设计并开发针对Na1.7通道的新型利多卡因类似物。
神经性疼痛（NP）被定义为源自神经系统内异常的慢性疼痛。电压门控钠通道在增强神经元兴奋性方面发挥着重要作用，因此作为开发治疗NP药物的关键靶点而具有重要意义。它由9种不同的亚型组成，其中Na1.7主要存在于背根神经节中，在NP的病理生理学中起关键作用。靶向Na1.7通道的选择性抑制剂在治疗NP方面具有更大的潜力，同时能将对其他钠通道亚型生理功能的干扰降至最低。
利用利多卡因类似物建立基于原子和场的三维（3D）定量构效关系（QSAR），以确定Na1.7抑制活性所需的结构特征。此外，通过将分子与Na1.7通道VSD4对接，随后进行吸收、分布、代谢和排泄（ADME）分析，研究了支架与Na1.7通道VSD4的分子相互作用。
3D QSAR研究表明，疏水基团的存在和空间参数提高了对Na1.7通道的特异性。对接分析显示，与参考药物利多卡因相比，4种化合物即A15、A14、A6和A5表现出最高的结合亲和力。此外，ADME预测表明这些化合物在口服生物利用度和溶解度方面具有良好的特性。
本研究为改善对Na1.7通道的特异性抑制提供了有价值的结构见解，有助于设计和开发新型的、Na1.7通道特异性抑制剂。
