Abstract
The α4β2 nAChR is implicated in a range of diseases and disorders including nicotine addiction, epilepsy and Parkinson’s and Alzheimer’s diseases. Designing α4β2 nAChR selective inhibitors could help define the role of the α4β2 nAChR in such disease states. In this study, we aimed to modify globular and ribbon α-conotoxin GID to selectively target the α4β2 nAChR through competitive inhibition of the α4(+)β2(−) or α4(+)α4(−) interfaces. The binding modes of the globular α-conotoxin [γ4E]GID with rat α3β2, α4β2 and α7 nAChRs were deduced using computational methods and were validated using published experimental data. The binding mode of globular [γ4E]GID at α4β2 nAChR can explain the experimental mutagenesis data, suggesting that it could be used to design GID variants. The predicted mutational energy results showed that globular [γ4E]GID is optimal for binding to α4β2 nAChR and its activity could not likely be further improved through amino-acid substitutions. The binding mode of ribbon GID with the (α4)3(β2)2 nAChR was deduced using the information from the cryo-electron structure of (α4)3(β2)2 nAChR and the binding mode of ribbon AuIB. The program FoldX predicted the mutational energies of ribbon [γ4E]GID at the α4(+)α4(−) interface, and several ribbon[γ4E]GID mutants were suggested to have desirable properties to inhibit (α4)3(β2)2 nAChR.
Highlights
We developed molecular models to evaluate the possibility of developing a selective inhibitor of α4β2 nAChR
Several substitutions of position 2 (R2D, R2E) increase selectivity at both receptors by 0.6–0.9 kcal/mol at the expense of a 0.8–1.3 kcal/mol decrease in affinity, representing a reasonable trade-off. These results suggest that rGID has potential for designing selective α4β2 nAChR inhibitors
Our models previously suggested that the ribbon isomer of α-conotoxins adopt a shape that is more compatible with the α/α interface than the α/β interface
Summary
The α4β2 nAChR is the most abundant and widely distributed neuronal nAChR and is a potential target for a range of neurological conditions and disorders [1], including nicotine addiction [2,3], epilepsy [4], Parkinson’s and Alzheimer’s disease [5]. The heteromeric α4β2 nAChR has two major stoichiometries with distinct functional properties: (α4) (β2). The two subtypes differ in their sensitivity to agonists, antagonists and allosteric modulators. Each subtype has distinct singlechannel conductance [8], mean open lifetime and activation-deactivation kinetics [9]. Both stoichiometries are associated with nicotine addiction and congenital epilepsy [10,11]
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