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Dmitry M. Hushpulian, Irina N. Gaisina, Sergey
V. Nikulin, Tatiana A. Chuba, Svyatoslav S. Savin, Irina G. Gazaryan, Vladimir I. Tishkov
High
throughput screening in drug discovery: problems and solutions
Abstract
Abstract. World-wide introduction of high throughput screening (HTS) methods in
drug discovery research did not result in the increased number of novel
medications on the market. We discuss novel trends in drug discovery that came
from the understanding that majority of diseases are multifactorial and that
one enzyme has many protein substrates. Hence, new approaches are focused on
development of drugs, which (1) trigger survival pathways to return the
organism to homeostatic balance, and (2) inhibit enzymes modifying histones or
transcription factors not at the active site, but by displacement of protein
substrates from the enzyme complexes. A good example for both approaches comes
from the development of activators of antioxidant defense. We analyze and
illustrate problems of commonly used in vitro HTS assays, and briefly
discuss advantages and limitations of small animal models. The novel approaches
are complementary to the standard HTS and do not substitute for testing in
mammals. Development of transgenic reporter mice to monitor drug effects by
means of in vivo imaging is extremely promising to select proper dosage
and administration regimes for full-range PK studies.
Key words: antioxidant response, reporter assay, Nrf2, Keap1, fluorescent
polarization, animal models
Copyright (C) Chemistry Dept., Moscow State University, 2002
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