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In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

Title
In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen
Author
남태규
Keywords
antifolates; cheminformatics; high-throughput screening; Plasmodium falciparum
Issue Date
2008-07
Publisher
NATL ACAD SCIENCES
Citation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 105, No. 26, Page. 9059-9064
Abstract
The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximate to 1.7 million compounds, we identified a diverse collection of approximate to 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 mu M). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.
URI
http://www.pnas.org/content/105/26/9059.shorthttp://repository.hanyang.ac.kr/handle/20.500.11754/104757
ISSN
0027-8424
DOI
10.1073/pnas.0802982105
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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