2005
DOI: 10.1021/ja052681+
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Modeling Multiple Species of Nicotine and Deschloroepibatidine Interacting with α4β2 Nicotinic Acetylcholine Receptor:  From Microscopic Binding to Phenomenological Binding Affinity

Abstract: A variety of molecular modeling, molecular docking, and first-principles electronic structure calculations were performed to study how the alpha4beta2 nicotinic acetylcholine receptor (nAChR) binds with different species of two typical agonists, (S)-(-)-nicotine and (R)-(-)-deschloroepibatidine, each of which is distinguished by different free bases and protonation states. On the basis of these results, predictions were made regarding the corresponding microscopic binding free energies. Hydrogen-bonding and ca… Show more

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Cited by 46 publications
(97 citation statements)
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“…This orientation is trans in the L-substrate bound to 6HLNO, stabilizing the conformer. Formation of the aromatic ring of the tertiary imine must be preceded by a movement of the pyrrolidine nitrogen into the pyramidal inversion transition state, which is a rapid process and inexpensive in energy as the carbon atoms remain in a puckered conformation (27). The inversion moves the nitrogen closer to the flavin, reducing the N1′-C4a distance from 4.1 Å to a similar value (about 3.3 Å) as in complexes of DAAO with active substrates (1C0P, 1EVI).…”
Section: Discussion Enzymatic Reaction States and Redox-dependent Conmentioning
confidence: 99%
“…This orientation is trans in the L-substrate bound to 6HLNO, stabilizing the conformer. Formation of the aromatic ring of the tertiary imine must be preceded by a movement of the pyrrolidine nitrogen into the pyramidal inversion transition state, which is a rapid process and inexpensive in energy as the carbon atoms remain in a puckered conformation (27). The inversion moves the nitrogen closer to the flavin, reducing the N1′-C4a distance from 4.1 Å to a similar value (about 3.3 Å) as in complexes of DAAO with active substrates (1C0P, 1EVI).…”
Section: Discussion Enzymatic Reaction States and Redox-dependent Conmentioning
confidence: 99%
“…The dominant molecular species under physiological conditions (pH 7.4) is a cationic structure, denoted by SRH, with the pyrrolidine nitrogen protonated [130]. The (S)-(−)-nicotine structure used in the DFT study [64] is the SRH species.…”
Section: Nicotine Oxidationmentioning
confidence: 99%
“…It has been known that both the protonated and deprotonated molecular species could bind with a protein. 34 Evaluation of the phenomenological binding of a protein with an amine compound should account for the microscopic binding of the protein with both the protonated and deprotonated molecular species. The phenomenological binding affinity is dependent on not only the microscopic binding affinities of the protonated and deprotonated molecular species, but also the pK a of the amine compound and the pH of the solution.…”
Section: Introductionmentioning
confidence: 99%