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Molecular recognition in nicotinic acetylcholine receptors: the importance of pi-cation interactions.

Abstract：

:We explore the significance of pi-cation interactions in the binding of ligands to nicotinic acetylcholine receptors. Specifically, the Austin method of semiempirical molecular orbital theory is utilized to estimate the interaction of aromatic amino acid side chains with the cation-containing heterocyclic ring fragments of nicotinic ligands. Variational interaction energies (E(i)) of side chain-ligand fragment pairs are shown to be distance-dependent and follow a Morse-like potential function. The tryptophan side chain shows the most pronounced interaction with the cation fragments, followed by tyrosine and phenylalanine. For a given side chain, cationic fragments exhibit characteristically different E(i) profiles, with the azabicyclo[2.2.1]heptane fragment of the potent nicotinic ligand epibatidine eliciting the greatest interaction energy of the study set. Most significantly, the minimum energy values calculated for numerous fragments correlate with the binding affinity of the parent ligands- we show this to be the case for heteropentameric (alpha4beta2) and homopentameric (alpha7) nicotinic acetylcholine receptor subtypes. Furthermore, intermolecular distances corresponding to the Morse-like potential minimum also correlate with high-affinity binding. A number of parallel calculations were conducted at the Hartree-Fock 6-31G ab initio level of theory in an effort to substantiate these findings.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Schmitt JD,Sharples CG,Caldwell WS

doi

10.1021/jm990093z

keywords:

subject

Has Abstract

pub_date

1999-08-12 00:00:00

pages

3066-74

issue

16

eissn

0022-2623

issn

1520-4804

pii

jm990093z

journal_volume

42

pub_type

杂志文章

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