Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 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 <inline-formula><math display="inline"><semantics><mi>α</mi>&...
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| Format: | Article |
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MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/15/7934 |
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| author | Francis A. Acquah Matthew Paramel Adama Kuta Syed R. Hussaini David R. Wallace Blaine H. M. Mooers |
| author_facet | Francis A. Acquah Matthew Paramel Adama Kuta Syed R. Hussaini David R. Wallace Blaine H. M. Mooers |
| author_sort | Francis A. Acquah |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:15:13Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:15:13Z |
| publishDate | 2021-07-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ad16310ef7a54a1f904ef75c614440d72023-11-22T05:40:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012215793410.3390/ijms22157934Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 Nicotinic Acetylcholine Receptor ComplexesFrancis A. Acquah0Matthew Paramel1Adama Kuta2Syed R. Hussaini3David R. Wallace4Blaine H. M. Mooers5Department of Biochemistry and Molecular Biology, University of Oklahoma of Health Sciences Center, Oklahoma City, OK 73104, USADepartment of Chemistry and Biochemistry, The University of Tulsa, Tulsa, OK 74104, USADepartment of Chemistry and Biochemistry, The University of Tulsa, Tulsa, OK 74104, USADepartment of Chemistry and Biochemistry, The University of Tulsa, Tulsa, OK 74104, USADepartment of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, USADepartment of Biochemistry and Molecular Biology, University of Oklahoma of Health Sciences Center, Oklahoma City, OK 73104, USASmoking-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.https://www.mdpi.com/1422-0067/22/15/7934validation of virtual screeninghetero-oligomer membrane protein modelingmembrane protein-drug complexesmembrane protein dynamics simulationssmoking cessationlung cancer |
| spellingShingle | Francis A. Acquah Matthew Paramel Adama Kuta Syed R. Hussaini David R. Wallace Blaine H. M. Mooers Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 Nicotinic Acetylcholine Receptor Complexes International Journal of Molecular Sciences validation of virtual screening hetero-oligomer membrane protein modeling membrane protein-drug complexes membrane protein dynamics simulations smoking cessation lung cancer |
| title | Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 Nicotinic Acetylcholine Receptor Complexes |
| title_full | Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 Nicotinic Acetylcholine Receptor Complexes |
| title_fullStr | Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 Nicotinic Acetylcholine Receptor Complexes |
| title_full_unstemmed | Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 Nicotinic Acetylcholine Receptor Complexes |
| title_short | Simulations of Promising Indolizidine—<i>α</i>6-<i>β</i>2 Nicotinic Acetylcholine Receptor Complexes |
| title_sort | simulations of promising indolizidine i α i 6 i β i 2 nicotinic acetylcholine receptor complexes |
| topic | validation of virtual screening hetero-oligomer membrane protein modeling membrane protein-drug complexes membrane protein dynamics simulations smoking cessation lung cancer |
| url | https://www.mdpi.com/1422-0067/22/15/7934 |
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