Simulations of Promising Indolizidine-α6-β2 Nicotinic Acetylcholine Receptor Complexes

Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as alpha 6 beta 2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block alpha 6 beta 2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for alpha 6 beta 2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of alpha 6 beta 2 nAChR that we derived from the recent crystal structure of alpha 4 beta 2 nAChR. We also screened the crystal structure of alpha 4 beta 2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards alpha 6 beta 2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.

Automated summary

Research has shown that Indolizidine (-)-237D has potential efficacy in targeting nicotine addiction-related alpha 6 beta 2* nAChR, with nine distinct analogs identified through screening and molecular dynamics simulations, which could serve as lead candidates for drug development in treating nicotine addiction.