Journal article
4D-QSAR Analysis of a Set of Propofol Analogues: Mapping Binding Sites for an Anesthetic Phenol on the GABAA Receptor
Journal of medicinal chemistry, Vol.45(15), pp.3210-3221
07/18/2002
DOI: 10.1021/jm010461a
PMID: 12109905
Abstract
A training set of 27 propofol (2,6-diisopropylphenol) analogues was used to construct four-dimensional (4D) quantitative structure−activity relationship (QSAR) models for three screens of biological activity: loss of righting reflex (LORR) in tadpoles, enhancement of agonist activity at the γ-aminobutyric acid type A (GABAA) receptor, and direct (agonist-independent) activation of the receptor. The three resulting 4D-QSAR models are almost identical in form, and all suggest three key ligand−receptor interaction sites. The formation of an intermolecular hydrogen bond involving the proton of the ligand −OH group is the most important binding interaction. A hydrophobic pocket binding interaction involving the six-substituent is the second most significant binding site, and a similar hydrophobic pocket binding interaction near the two-substituent is the third postulated binding site from the 4D-QSAR models. A test set of eight compounds was used to evaluate the tadpole LORR 4D-QSAR model. Those compounds highly congeneric to the training set compounds were accurately predicted. However, compounds exploring substituent sites and/or electronic structures different from the training set were less well-predicted. Overall, the results show a striking similarity between the models of the sites responsible for anesthesia and those mediating effects of the training set of propofol analogues on the GABAA receptor; it follows that the GABAA receptor is therefore the likely site of propofol's anesthetic action.
Details
- Title: Subtitle
- 4D-QSAR Analysis of a Set of Propofol Analogues: Mapping Binding Sites for an Anesthetic Phenol on the GABAA Receptor
- Creators
- Matthew D KrasowskiXuan HongA. J HopfingerNeil L Harrison - Weill Cornell Medicine
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.45(15), pp.3210-3221
- DOI
- 10.1021/jm010461a
- PMID
- 12109905
- NLM abbreviation
- J Med Chem
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Publisher
- American Chemical Society
- Language
- English
- Date published
- 07/18/2002
- Academic Unit
- Pathology
- Record Identifier
- 9984047977502771
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