Recent advances in computational studies on voltage‐gated sodium channels: Drug design and mechanism studies

Abstract

Voltage-gated sodium channels (VGSCs/Na v s), which control the flow of Na + and affect the generation of action potentials (APs), have been regarded as essential targets for many diseases. The biological and pharmacological functions of VGSCs have been extensively studied and many efforts have been made to discover and design ligands of VGSCs as potential therapies. Here, we summarize the recent and representative studies of VGSCs from the perspective of computer-aided drug design (CADD) and molecular modeling, including the structural biology of VGSCs, virtual screening and drug design toward VGSCs based on CADD, and functional studies using molecular modeling technologies. Furthermore, we conclude the achievements that have been made in the field of VGSCs and discuss the shortcomings found in previous studies. We hope that this review can provide some inspiration and reference for future investigations of VGSCs and drug design. This article is categorized under:Structure and Mechanism > Computational Biochemistry and Biophysicscomputer-aided drug design, molecular dynamic simulation, structural biology, voltage-gated sodium channels | INTRODUCTIONVoltage-gated sodium channels (VGSCs/Na v s) are widely expressed in eukaryotes and prokaryotes, and play especially important roles in the generation and propagation of action potentials (APs). 1,2 Since Hodgkin and Huxley successfully recorded the first Na + -based APs from the giant axons of the squid Loligo, 3,4 researchers came to realize the important role of VGSCs in nerve impulse conduction, which opened a new door for VGSCs studies. To date, 10 subtypes of VGSCs (Na v 1.1-Na v 1.9 and Nax) have been found in mammals, and each subtype has its own unique functions (Table S1). Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6 are primarily expressed in the central nervous system (CNS), and associated with many diseases such as epilepsy, migraine, autism, and ataxia. 5 Na v 1.4 is predominantly expressed in skeletal

A Combined Ligand- and Structure-Based Virtual Screening To Identify Novel NaV1.2 Blockers: In Vitro Patch Clamp Validation and In Vivo Anticonvulsant Activity

“…The appropriate in silico (and experimental) validations of the developed models are not always reported in previous VS campaigns for NaVs modulators. 12 To the extent of our knowledge, this investigation is the first example of the successful application of sequential VS with validated protocols against the NaV1.2 channel. The VS using the two final models was performed in parallel over the DrugBank5.1 database, 13 which includes approved and experimental phase drugs, and nutraceuticals.…”

“…Special attention was given to the initial steps of the VS, that is, the curation of the data, the validation of the algorithms, and the systematic exploration of several docking conditions for VS, including the analysis of target conformations. The appropriate in silico (and experimental) validations of the developed models are not always reported in previous VS campaigns for NaVs modulators . To the extent of our knowledge, this investigation is the first example of the successful application of sequential VS with validated protocols against the NaV1.2 channel.…”