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 [Formula: see text] 6 [Formula: see text] 2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block [Formula: see text] 6 [Formula: see text] 2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for [Formula: see text] 6 [Formula: see text] 2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of [Formula: see text] 6 [Formula: see text] 2 nAChR that we derived from the recent crystal structure of [Formula: see text] 4 [Formula: see text] 2 nAChR. We also screened the crystal structure of [Formula: see text] 4 [Formula: see text] 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 [Formula: see text] 6 [Formula: see text] 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.