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Biochem Biophys Res Commun. 2014 Mar 21;445(4):724-33. doi: 10.1016/j.bbrc.2014.01.179. Epub 2014 Feb 10.

Drug screening strategy for human membrane proteins: from NMR protein backbone structure to in silica- and NMR-screened hits.

Author information

1
Department of Chemistry and Biochemistry, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
2
Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037, USA; Joint Center for Biosciences, 301-B, Songdo Smart Valley 214, Songdo-dong, Yeonsu-ku, Incheon 406-840, Republic of Korea.
3
Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037, USA.
4
Department of Chemistry and Biochemistry, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Howard Hughes Medical Institute, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; NSF Center for Theoretical Biological Physics, National Biomedical Computation Resource, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
5
Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037, USA; Joint Center for Biosciences, 301-B, Songdo Smart Valley 214, Songdo-dong, Yeonsu-ku, Incheon 406-840, Republic of Korea; Drug Discovery Collaboratory, Carlsbad, CA 92008, USA. Electronic address: choe@salk.edu.

Abstract

About 8000 genes encode membrane proteins in the human genome. The information about their druggability will be very useful to facilitate drug discovery and development. The main problem, however, consists of limited structural and functional information about these proteins because they are difficult to produce biochemically and to study. In this paper we describe the strategy that combines Cell-free protein expression, NMR spectroscopy, and molecular DYnamics simulation (CNDY) techniques. Results of a pilot CNDY experiment provide us with a guiding light towards expedited identification of the hit compounds against a new uncharacterized membrane protein as a potentially druggable target. These hits can then be further characterized and optimized to develop the initial lead compound quicker. We illustrate such "omics" approach for drug discovery with the CNDY strategy applied to two example proteins: hypoxia-induced genes HIGD1A and HIGD1B.

KEYWORDS:

Computational docking; Human membrane proteins; Molecular dynamics; NMR screening

PMID:
24525125
PMCID:
PMC4457379
DOI:
10.1016/j.bbrc.2014.01.179
[Indexed for MEDLINE]
Free PMC Article
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