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1.  4D-QSAR Analysis of a Set of Propofol Analogues: Mapping Binding Sites for an Anesthetic Phenol on the GABAA Receptor 
Journal of medicinal chemistry  2002;45(15):3210-3221.
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.
PMCID: PMC2864546  PMID: 12109905

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