A high-throughput approach for identification of novel general anesthetics.
Anesthetic development has been a largely empirical process. Recently, we described a GABAergic mimetic model system for anesthetic binding, based on apoferritin and an environment-sensitive fluorescent probe. Here, a competition assay based on 1-aminoanthracene and apoferritin has been taken to a high throughput screening level, and validated using the LOPAC(1280) library of drug-like compounds. A raw hit rate of approximately 15% was reduced through the use of computational filters to yield an overall hit rate of approximately 1%. These hits were validated using isothermal titration calorimetry. The success of this initial screen and computational triage provides feasibility to undergo a large scale campaign to discover novel general anesthetics.
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Wendy A
WA
Lea
Jin
J
Xi
Ajit
A
Jadhav
Louis
L
Lu
Christopher P
CP
Austin
Anton
A
Simeonov
Roderic G
RG
Eckenhoff
D000768:Anesthesia, General / Q000379:methods; D018681:Anesthetics, General / Q000627:therapeutic use*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001052:Apoferritins / Q000737:chemistry; D002151:Calorimetry / Q000379:methods; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006736:Horses; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013154:Spleen / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000295:instrumentation* / Q000379:methods*
D018681:Anesthetics, General; D000873:Anthracenes; C049062:1-aminoanthracene; D001052:Apoferritins