Computational Design of High-Affinity Blockers for Sodium Channel NaV1.2 from μ-Conotoxin KIIIA.

Guangsi Meng,Serdar Kuyucak

doi:10.3390/md20020154

Abstract

The voltage-gated sodium channel subtype 1.2 (NaV1.2) is instrumental in the initiation of action potentials in the nervous system, making it a natural drug target for neurological diseases. Therefore, there is much pharmacological interest in finding blockers of NaV1.2 and improving their affinity and selectivity properties. An extensive family of peptide toxins from cone snails (conotoxins) block NaV channels, thus they provide natural templates for the design of drugs targeting NaV channels. Unfortunately, progress was hampered due to the absence of any NaV structures. The recent determination of cryo-EM structures for NaV channels has finally broken this impasse. Here, we use the NaV1.2 structure in complex with μ-conotoxin KIIIA (KIIIA) in computational studies with the aim of improving KIIIA’s affinity and blocking capacity for NaV1.2. Only three KIIIA amino acid residues are available for mutation (S5, S6, and S13). After performing molecular modeling and simulations on NaV1.2–KIIIA complex, we have identified the S5R, S6D, and S13K mutations as the most promising for additional contacts. We estimate these contacts to boost the affinity of KIIIA for NaV1.2 from nanomole to picomole domain. Moreover, the KIIIA[S5R, S6D, S13K] analogue makes contacts with all four channel domains, thus enabling the complete blocking of the channel (KIIIA partially blocks as it has contacts with three domains). The proposed KIIIA analogue, once confirmed experimentally, may lead to novel anti-epileptic drugs.

Highlights

The voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials, and play a key role in membrane excitability and electrical signaling [1,2,3]
We start with a comparison of the NaV1.2–KIIIA binding mode that was obtained from the molecular dynamics (MD) simulations with that of the cryo-EM structure (Table 1)
Most of the N–O distances that were obtained from MD were in good agreement with the experimental values that are in Table 1, especially when the pair of atoms are at contact distances of ~3 Å when the interaction is strongest

Summary

Introduction

The voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials, and play a key role in membrane excitability and electrical signaling [1,2,3]. Once a toxin is selected as a potential drug lead for a target ion channel, it is important to improve its affinity and selectivity for the target to reduce the dosage and avoid side effects. For toxin peptides, this can be achieved by designing analogues of the toxin through mutations of selected residues, which are predicted to make further contacts with the channel residues. After the S5R mutation, R5 makes contact with a domain IV residue, resulting in a complete block of the pore These results suggest that the proposed KIIIA analogues could provide valuable leads in the development of therapeutics for epilepsy

Results and Discussion

D11 H12 K13

Conclusions