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J Comput Aided Mol Des. 2005 Jan;19(1):1-15.

Protonation-induced stereoisomerism in nicotine: conformational studies using classical (AMBER) and ab initio (Car-Parrinello) molecular dynamics.

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  • 1Targacept, Inc., 200 East First Street, Suite 300, Winston-Salem, NC 27101-4165, USA. phil.hammond@targacept.com

Abstract

A variety of biologically active small molecules contain prochiral tertiary amines, which become chiral centers upon protonation. S-nicotine, the prototypical nicotinic acetylcholine receptor agonist, produces two diastereomers on protonation. Results, using both classical (AMBER) and ab initio (Car-Parrinello) molecular dynamical studies, illustrate the significant differences in conformational space explored by each diastereomer. As is expected, this phenomenon has an appreciable effect on nicotine's energy hypersurface and leads to differentiation in molecular shape and divergent sampling. Thus, protonation induced isomerism can produce dynamic effects that may influence the behavior of a molecule in its interaction with a target protein. We also examine differences in the conformational dynamics for each diastereomer as quantified by both molecular dynamics methods.

PMID:
16059663
[PubMed - indexed for MEDLINE]
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