Screening in a spirit haunted world.
High-throughput screening (HTS) campaigns can be dominated by hits that ultimately turn out to be non-drug-like. These "nuisance" compounds often behave strangely, with steep dose-response curves, absence of clear structure-activity relationships, and high sensitivity to assay conditions. Several mechanisms contribute to these artifacts, including chemically reactive molecules, those that absorb light in assays and those that affect redox conditions. One of the most common mechanisms behind artifactual inhibition is discussed in this review: at micromolar concentrations organic molecules can aggregate to form particles in aqueous buffers, and these aggregates can sequester and thereby inhibit protein targets. Aggregation-based inhibition is baffling from a chemical perspective, but viewed biophysically such behavior is expected. The range of molecules that behave this way, their rapid detection in a screening environment and their possible biological implications will be considered here.
Shoichet
Brian K
BK
Department of Pharmaceutical Chemistry, University of California-San Francisco, 1700 4th St., Byers Hall Room 508D, San Francisco, CA 94158, USA. shoichet@cgl.ucsf.edu
D016477:Artifacts; D001681:Biological Assay / Q000379:methods; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D003102:Colloids; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D011487:Protein Conformation; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism
D003102:Colloids; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D002918:Chymotrypsin; D001618:beta-Lactamases