HIGH THROUGHPUT SCREENING IN DRUG DISCOVERY: PROBLEMS AND SOLUTIONS

Author:

Hushpulian Dmitry M.1,Gaisina Irina N.2,Nikulin Sergey V.3,Chubar Tatiana A.4,Savin Svyatoslav S.4,Gazaryan Irina G.5,Tishkov Vladimir I.6

Affiliation:

1. Bach Institute of Biochemistry; National Research University “Higher School of Economics”

2. University of Illinois at Chicago

3. National Research University “Higher School of Economics”

4. Lomonosov Moscow State University

5. National Research University “Higher School of Economics”; Lomonosov Moscow State University

6. Bach Institute of Biochemistry; Lomonosov Moscow State University

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 briefl y 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.

Funder

Russian Science Foundation

Publisher

Moscow University Press

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