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.
Krasowski
Matthew D
MD
Department of Anesthesia and Critical Care, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Hong
Xuan
X
Hopfinger
A J
AJ
Harrison
Neil L
NL
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