title: Drug screening strategy for human membrane proteins: from NMR protein backbone structure to in silica- and NMR-screened hits.
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.
authors: Department of Chemistry and Biochemistry, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Steffen
authors: S
authors: Lindert
authors: 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.
authors: Innokentiy
authors: I
authors: Maslennikov
authors: Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037, USA.
authors: Ellis J C
authors: EJ
authors: Chiu
authors: Department of Chemistry and Biochemistry, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Levi C
authors: LC
authors: Pierce
authors: 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.
authors: J Andrew
authors: JA
authors: McCammon
authors: 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.
authors: Senyon
authors: S
authors: Choe
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D024101:Mitochondrial Proteins; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011487:Protein Conformation
chemical_list: C405619:HIGD1A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins
keywords: Computational docking; Human membrane proteins; Molecular dynamics; NMR screening