4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor.
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 gamma-aminobutyric acid type A (GABA(A)) 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 GABA(A) receptor; it follows that the GABA(A) receptor is therefore the likely site of propofol's anesthetic action.
Department of Anesthesia and Critical Care, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Matthew D
MD
Krasowski
Xuan
X
Hong
A J
AJ
Hopfinger
Neil L
NL
Harrison
D000465:Algorithms; D018681:Anesthetics, General / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007814:Larva; D008024:Ligands; D008958:Models, Molecular; D015742:Propofol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D021122:Protein Subunits; D021281:Quantitative Structure-Activity Relationship; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000502:physiology
D018681:Anesthetics, General; D018690:Excitatory Amino Acid Agonists; D008024:Ligands; D021122:Protein Subunits; D011963:Receptors, GABA-A; D015742:Propofol