Drug screening strategy for human membrane proteins: From NMR protein backbone structure to in silica- and NMR-screened hits |
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| Authors: | Steffen Lindert Innokentiy Maslennikov Ellis J.C. Chiu Levi C. Pierce J. Andrew McCammon Senyon Choe |
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| Affiliation: | 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;3. Joint Center for Biosciences, 301-B, Songdo Smart Valley 214, Songdo-dong, Yeonsu-ku, Incheon 406-840, Republic of Korea;4. Howard Hughes Medical Institute, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA;5. NSF Center for Theoretical Biological Physics, National Biomedical Computation Resource, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA;6. Drug Discovery Collaboratory, Carlsbad, CA 92008, USA |
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| 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. |
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| Keywords: | hIMPs, human integral membrane proteins CF, cell-free HI, hypoxia-induced MD, molecular dynamics DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine LMPG, 1-myristoyl-2-hydroxy-sn-glycero-3-[phospho-rac-(1-glycerol) |
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