Three-dimensional Quantitative Structure-activity Relationship, Molecular Docking and Absorption, Distribution, Metabolism, and Excretion Studies of Lidocaine Analogs Pertaining to Voltage-gated Sodium Channel Nav1.7 Inhibition for the Management of Neuropathic Pain.

AIM: This study aims to design and develop novel lidocaine analogs specific for the Nav1.7 channel using in silico approaches.

BACKGROUND

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 Nav1.7 predominantly found in the dorsal root ganglion, playing a crucial role in the pathophysiology of NP. The selective inhibitors targeting the Nav1.7 channel hold greater potential for treating NP while minimizing interference with the physiological functions of other sodium channel isoforms.

METHODS

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 Nav1.7 inhibitory activities. Further, the molecular interaction of the scaffold with the Nav1.7 channel VSD4 was studied by docking the molecules with it followed by absorption, distribution, metabolism, and excretion (ADME) analysis.

RESULTS

The 3D QSAR studies revealed that the presence of hydrophobic groups and steric parameters heightened the specificity for Nav1.7 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.

CONCLUSION

This research offers valuable structural insights to improve the specific inhibition of the Nav1.7 channel, facilitating the design and development of novel, Nav1.7 channel-specific inhibitors.