Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 Nicotinic Acetylcholine Receptor Complexes

• Main Authors: Francis A. Acquah, Matthew Paramel, Adama Kuta, Syed R. Hussaini, David R. Wallace, Blaine H. M. Mooers
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: International Journal of Molecular Sciences
• Subjects: validation of virtual screening; hetero-oligomer membrane protein modeling; membrane protein-drug complexes; membrane protein dynamics simulations; smoking cessation; lung cancer
• Online Access: https://www.mdpi.com/1422-0067/22/15/7934
• ISSN: 1661-6596; 1422-0067

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 <inline-formula><math display="inline"><semantics><mi>α</mi></semantics></math></inline-formula>6<inline-formula><math display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block <inline-formula><math display="inline"><semantics><mi>α</mi></semantics></math></inline-formula>6<inline-formula><math display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for <inline-formula><math display="inline"><semantics><mi>α</mi></semantics></math></inline-formula>6<inline-formula><math display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of <inline-formula><math display="inline"><semantics><mi>α</mi></semantics></math></inline-formula>6<inline-formula><math display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>2 nAChR that we derived from the recent crystal structure of <inline-formula><math display="inline"><semantics><mi>α</mi></semantics></math></inline-formula>4<inline-formula><math display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>2 nAChR. We also screened the crystal structure of <inline-formula><math display="inline"><semantics><mi>α</mi></semantics></math></inline-formula>4<inline-formula><math display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>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 <inline-formula><math display="inline"><semantics><mi>α</mi></semantics></math></inline-formula>6<inline-formula><math display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>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.