Homogeneous pharmacologic and cell-based screens provide diverse strategies in drug discovery: somatostatin antagonists as a case study.
The development of high throughput, homogeneous pharmacologic and functional assays and their implementation in screening combinatorial libraries has increased the pace of stochastic drug discovery in recent years. New, noninvasive approaches involving radiometric proximity assays, an array of fluorescence-based technologies, and reporter gene constructs in mammalian and nonmammalian systems are providing more options for the selection of specific therapeutic targets. The increasing sophistication of homogeneous assay designs has also served as a springboard to better lead validation in drug discovery initiatives. This review examines these approaches in the context of new drug discovery strategies which combine a growing repertoire of high throughput screening techniques. The utility and importance of cell-based assays vis-a-vis pharmacologic (cell-free) assays is considered with specific reference given to yeast-based functional screens and homogeneous binding methodologies used to search for somatostatin antagonists and other potential growth hormone secretagogues. Also considered is the custom tailoring of specific chemical libraries which provide yet another level of target selectivity. The advantages and shortcomings of these various technologies are discussed in light of emerging trends toward higher throughput and nanoscale formats which are pushing the limits of measurable response at the cellular and molecular level.
Zysk
J R
JR
NovaScreen, A Division of Oceanix Biosciences Corp., Hanover, MD 21076, USA.
Baumbach
W R
WR
D000818:Animals; D002474:Cell-Free System; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D019151:Peptide Library; D013004:Somatostatin / Q000037:antagonists & inhibitors*; D013050:Spectrometry, Fluorescence
D019151:Peptide Library; D013004:Somatostatin