title: Partial activation of α7 nicotinic acetylcholine receptors: insights from molecular dynamics simulations.
abstract: Nicotinic acetylcholine receptors (nAChRs) are drug targets for neuronal disorders and diseases. Partial agonists for nAChRs are currently being developed as drugs for the treatment of neurological diseases for their relative safety originated from reduced excessive stimulation. In the current study, molecular docking, molecular dynamics simulations and binding energy calculations were performed to theoretically investigate the interactions between the partial agonists, 4-OH-DMXBA and tropisetron with α7-nAChR. The results suggest that the partial agonists 4-OH-DMXBA and tropisetron bind with α7-nAChR in a binding mode similar to that with AChBP. The non-conserved residues in the binding sites contribute to the orientation deviation of these partial agonists from their orientation in AChBP. Energy calculation and decomposition using MM-GB/SA suggests that the van der Waals term (ΔE(VDW)) is the main driving force for the binding of the partial agonists to α7-nAChR. The molecular dynamics simulations showed that the opening of the C-loop binding with the partial agonists is in-between the openings for the binding with the full agonist and in the apo state. This conformation difference for the C-loop sheds light on the partial agonism of nAChR.
authors.affiliation: Key Laboratory of Systems Bioengineering, Ministry of Education, Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.
authors.forename: Caijuan
authors.initials: C
authors.lastname: Shi
authors.forename: Rilei
authors.initials: R
authors.lastname: Yu
authors.forename: Shengjuan
authors.initials: S
authors.lastname: Shao
authors.forename: Yanni
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000737:chemistry*; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018722:Nicotinic Agonists / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics; D000077526:Tropisetron; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C428944:AChBP protein, Lymnaea; D001597:Benzylidene Compounds; D002352:Carrier Proteins; C579167:Chrna7 protein, human; D007211:Indoles; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077526:Tropisetron; C088936:3-(2,4-dimethoxybenzylidene)anabaseine