Computer-based model for identification and characterization for non-competitive inhibitors of nicotinic acetylcholine receptors and related ligand-gated ion channel receptors

a technology characterization model, which is applied in the field of computer-based model for identification and characterization of non-competitive inhibitors of nicotinic acetylcholine receptors and related ligand-gated ion channel receptors, can solve the problems of ineffective rapid screening of chemical libraries of drug candidates, time-consuming nci identification methods, and inability to detect interactions between channels,

Inactive Publication Date: 2004-10-14
HEALTH & HUMAN SERVICES GOVERNMENT OF THE UNITED STATES OF AMERICA REPRESENTED BY THE SEC DEPT OF THE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Non-competitive inhibition of the nAChR can be responsible for severe adverse drug effects.
Classical methods of NCI identification are time consuming and not effective in rapid screening of chemical libraries of drug candidates.
However, none of those models were used to investigate interaction with channel blockers.
The functional determination and characterization of a NCI of an LGIC is very complex and time consuming.

Method used

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  • Computer-based model for identification and characterization for non-competitive inhibitors of nicotinic acetylcholine receptors and related ligand-gated ion channel receptors
  • Computer-based model for identification and characterization for non-competitive inhibitors of nicotinic acetylcholine receptors and related ligand-gated ion channel receptors
  • Computer-based model for identification and characterization for non-competitive inhibitors of nicotinic acetylcholine receptors and related ligand-gated ion channel receptors

Examples

Experimental program
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Effect test

example 1

Modeling of the Lumen of a .alpha.3.beta.4 nAChR and Docking of a Putative NCI

[0061] The molecular model of a .delta.-M2--nAChR transmembrane channel determined by frozen state NMR was used as the template for further modification (atomic coordinates were found in Protein Data Bank--PDB id: 1EQ8). This model represents a channel that mimics the transmembrane arrangement of known LGICs (Opella S. J., Marassi F. M., Gesell J. J., Valente A. P., Kim Y., Oblatt-Montal M., Montal M., (1999) Structures of the M2 channel-lining segments from nicotinic acetylcholine and NMDA receptors by NMR spectroscopy. Nat. Struct. Biol. 6:374-9). The model channel consisted of 5 uniform polypeptides oriented around a central pore. The amino-acid sequence of this polypeptide is analogous to the sequence of transmembrane M2 segment of .delta. subunit of nAChR found in Torpedo californica. Table 1 presents the primary structure of this .delta.-M2-segment.

[0062] In the .delta.-M2--nAChR transmembrane channe...

example 2

Chromatographic Assay of NCI Activity

[0080] Chromatographic studies based on immobilized nAChRs were performed to characterize ligand binding for broad groups of compounds. In order to further understand the mechanistic action of NCIs on the molecular level, the model of the transmembrane domain of the .alpha.3.beta.4 nAChR was built and used for computer simulations of docking inhibitors into the receptor. The entire approach allowed the classification of NCIs in terms of their functional effectiveness.

[0081] FIG. 9 presents compounds tested on an .alpha.3.beta.4 nAChR column. The chemicals can be divided into several subgroups. The first group contains drugs from different origin, which are well known as non-competitive inhibitors of nAChRs. The second group is of the dextromethorphan family, levomethorphan, dextromethorphan and its analogues, and the final group is verapamil, its congeners, and metabolites. In order to properly assess the influence of non-specific retention, five...

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Abstract

A computer readable medium holding data of a molecular model of a ligand-gated ion channel receptor and / or a computer system for modeling said receptor are provided by the instant invention. The molecular model can be used to design novel compounds having activity as non-competitive inhibitors of the ion channel. A preferred embodiment of the invention relates to nicotinic acetylcholine receptors. Compounds having activity as non-competitive inhibitors of ligand-gated ion channel receptors and methods for inhibiting the receptor and treating diseases or disorders mediated by function of the receptor are also disclosed.

Description

[0001] The present application includes an appended Sequence Listing of 15 amino acid sequences and Appendices 1 to 3 providing computer programming scripts and parameter files.FIELD OF THE INVENTION[0002] The present invention relates to a computer system for generating molecular models of ligand-gated ion channels and in particular, molecular models of the inner lumen of a ligand-gated ion channel and associated binding pockets. The present invention further relates to a computer system simulating interaction of the computer-based model of the ligand-gated channel and non-competitive inhibitor compounds for identification and characterization of non-competitive inhibitors and to inhibitors compounds so discovered. The present invention also relates to methods for treating various disorders related to ligand-gated ion channel receptor function.BACKGROUND OF THE INVENTION[0003] Ligand-gated ion channels are currently a popular target for drug discovery in the pharmaceutical industry...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/00A61K31/43A61K38/00C07K1/00C07K14/705G06F19/00G16B15/30G16B20/00
CPCA61K31/00A61K31/43A61K38/00C07K1/00C07K14/70571G06F19/16G06F19/18G16B15/00G16B20/00A61P25/18A61P25/24A61P25/28A61P25/34G16B15/30
Inventor WAINER, IRVING W.JOZWIAK, KRZYSZTOFRAVICHANDRAN, SARANGANCOLLINS, JACK R.
Owner HEALTH & HUMAN SERVICES GOVERNMENT OF THE UNITED STATES OF AMERICA REPRESENTED BY THE SEC DEPT OF THE
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