680
Views
1
CrossRef citations to date
0
Altmetric
Research Article

A virtual high-throughput screening approach to the discovery of novel inhibitors of the bacterial leucine transporter, LeuT

, , , , , & show all
Pages 184-194 | Received 16 Mar 2012, Accepted 12 Jun 2012, Published online: 21 Aug 2012

References

  • Chae PS, Rasmussen SGF, Rana RR, Gotfryd K, Chandra R, Goren MA, 2010. Maltose-neopentyl glycol (MNG) amphiphiles for solubilization, stabilization and crystallization of membrane proteins. Nat Methods 7:1003–1008.
  • Cuatrecasas P. 2006. Drug discovery in jeopardy. J Clin Investig 116:2837–2842.
  • Davies M, Heikkila T, Mcconkey GA, Fishwick CWG, Parsons MR, Johnson AP. 2009. Structure-based design, synthesis, and characterization of inhibitors of human and plasmodium falciparum dihydroorotate dehydrogenases. J Med Chem 52:2683–2693.
  • Fox S, Farr-Jones S, Sopchak L, Boggs A, Nicely HW, Khoury R, 2006. High-throughput screening: Update on practices and success. J Biomol Screen 11:864–869.
  • Giacomini KM, Huang S-M, Tweedie DJ, Benet LZ, Brouwer KLR, Chu X, & 2010. Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236.
  • Gillet VJ, Myatt G, Zsoldos Z, Johnson AP. 1995. SPROUT, HIPPO and CAESA: Tools for de novo structure generation and estimation of synthetic accessibility. Perspect Drug Discov Des 3:34–50.
  • Gillet VJ, Newell W, Mata P, Myatt G, Sike S, Zsoldos Z, 1994. SPROUT – recent developments in the de-novo design of molecules. J Chem Info Computer Sci 34:207–217.
  • Jardetzk O. 1966. Simple allosteric model for membrane pumps. Nature 211:969–970.
  • Law JMS, Fung DYK, Zsoldos Z, Simon A, Szabo Z, Csizmadia IG, 2003. Validation of the SPROUT de novo design program. J Mol Struct-Theochem 666:651–657.
  • Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. 2007. Drugs for bad bugs: Confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6:29–40.
  • Quick M, Javitch JA. 2007. Monitoring the function of membrane transport proteins in detergent-solubilized form. Proc Natl Acad Sci USA 104:3603–3608.
  • Quick M, Winther AML, Shi L, Nissen P, Weinstein H, Javitch JA. 2009. Binding of an octylglucoside detergent molecule in the second substrate (S2) site of LeuT establishes an inhibitor-bound conformation. Proc Natl Acad Sci USA 106:5563–5568.
  • Ryan RM, Mindell JA. 2007. The uncoupled chloride conductance of a bacterial glutamate transporter homolog. Nat Struct Mol Biol 14:365–371.
  • Schwab CH. 2010. Conformations and 3D pharmacophore searching. Drug Discov Today Technol 7:e245–e253.
  • Shi L, Quick M, Zhao YF, Weinstein H, Javitch JA. 2008. The mechanism of a neurotransmitter: sodium symporter – inward release of Na+ and substrate is triggered by substrate in a second binding site. Mol Cell 30:667–677.
  • Simmons KJ, Chopra I, Fishwick CWG. 2010. Structure-based discovery of antibacterial drugs. Nat Rev Microbiol 8:501–510.
  • Singh SK, Piscitelli CL, Yamashita A, Gouaux E. 2008. A competitive inhibitor traps LeuT in an open-to-out conformation. Science 322:1655–1661.
  • Singh SK, Yamashita A, Gouaux E. 2007. Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448:952–956.
  • Torres J, Stevens TJ, Samso M. 2003. Membrane proteins: The ‘Wild West' of structural biology. Trends Biochem Sci 28:174.
  • Verkman AS. 2012. Aquaporins in clinical medicine. In: Caskey CT, Austin CP, Hoxie JA, editors. Annual Review of Medicine. Vol. 63. Palo Alto, CA: Annual Reviews.
  • Wacker SJ, Jurkowski W, Rolland J-F, Simmons KJ, Fishwick C, Johnson P, 2012. Identification of novel selective inhibitors of the potassium channel Kv1.1–1.2(3) by high-throughput virtual screening and electrophysiology. ChemMedChem.
  • Weyand S, Shimamura T, Yajima S, Suzuki S, Mirza O, Krusong K, 2008. Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter. Science 322:709–713.
  • Woon ECY, Zervosen A, Sauvage E, Simmons KJ, Zivec M, Inglis SR, 2011. Structure guided development of potent reversibly binding penicillin binding protein inhibitors. ACS Med Chem Lett 2:219–223.
  • Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E. 2005. Crystal structure of a bacterial homologue of Na+/Cl−dependent neurotransmitter transporters. Nature 437:215–223.
  • Yi Mok N, Chadwick J, Kellett KAB, Hooper NM, Johnson AP, Fishwick CWG. 2009. Discovery of novel non-peptide inhibitors of BACE-1 using virtual high-throughput screening. Bioorg Med Chem Lett 19:6770–6774.
  • Zsoldos Z, Reid D, Simon A, Sadjad BS, Johnson AP. 2006. eHITS: An innovative approach to the docking and scoring function problems. Curr Protein Pept Sci 7:421–435.
  • Zsoldos Z, Reid D, Simon A, Sadjad SB, Johnson AP. 2007. eHiTS: A new fast, exhaustive flexible ligand docking system. J Mol Graph Model 26:198–212.
  • Zsoldos Z, Szabo I, Szabo Z, Johnson AP. 2003. Software tools for structure based rational drug design. J Mol Struct Theochem 666:659–665.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.