Modeling Differential Binding of α4β2 Nicotinic Acetyicholine Receptor with Agonists and Antagonists.
Three-dimensional structures of both the open- and closed-channel states of α4β2 receptor have been modeled and used to study their binding with representative agonists and antagonists. The obtained binding structures and free energies consistently reveal that antagonists bind more favorably with th...
| Publicado en: | Journal of the American Chemical Society Vol. 130; no. 49; pp. 16691 - 16697 |
|---|---|
| Autores principales: | , , |
| Formato: | Artículo |
| Publicado: |
American Chemical Society
12/10/2008
|
| Materias: | |
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=35760554&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 35760554 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 12/10/2008 vid: 130 iid: 49 pid: 997 pub: American Chemical Society artinfo: ui: 35760554 10.1021/ja8055326 ppf: 16691 ppct: 6 formats: tig: atl: Modeling Differential Binding of α4β2 Nicotinic Acetyicholine Receptor with Agonists and Antagonists. aug: au: Xiaoqin Huang Fang Zheng Chang-Guo Zhan affil: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536 su: Computer network protocols Ligand binding (Biochemistry) Nicotinic receptors Chemical inhibitors Chemical agonists Biochemistry Therapeutics sug: subj: Computer network protocols Ligand binding (Biochemistry) Nicotinic receptors Chemical inhibitors Chemical agonists Biochemistry Therapeutics ab: Three-dimensional structures of both the open- and closed-channel states of α4β2 receptor have been modeled and used to study their binding with representative agonists and antagonists. The obtained binding structures and free energies consistently reveal that antagonists bind more favorably with the closed- channel state and agonists bind more favorably with the open-channel state. The computational insights have led us to propose a computational strategy and protocol predicting whether a receptor ligand is an agonist or antagonist. Using the computational protocol, one only needs to calculate the relative binding free energies for a ligand binding with the open- and closed-channel structures. The ligand is predicted to be an agonist if the binding free energy calculated for the ligand binding with the open-channel state is significantly lower than that for its binding with the closed-channel state. If the binding free energy of a ligand with the open-channel state is higher than that with the closed-channel, the ligand is predicted to be an antagonist. The binding free energies calculated for all of the ligands binding with their most favorable channel states of the receptor are all close to the corresponding experimentally derived binding free energies. The new computational insights obtained and novel computational strategy and protocol proposed in this study are expected to be valuable in structure-based rational design of novel agonists/antagonists of nAChRs as therapeutic agents. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2008 holdings: @attributes: islocal: N |
|---|