Molecular modeling and ligand docking for solute carrier (SLC) transporters

Current Topics in Medicinal Chemistry

Volumn 13, Issue 6 7, 2013, Pages 843-856

  Schlessinger, Avner ^a,b,c   Khuri, Natalia ^a,b   Giacomini, Kathleen M ^a,b   Sali, Andrej ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c MOUNT SINAI SCHOOL OF MEDICINE   (United States)

Author keywords

Comparative modeling; Ligand docking; Membrane transporter; Protein function prediction; Structure based ligand discovery

Indexed keywords

4 AMINOBUTYRIC ACID CARRIER; AMINO ACID TRANSPORTER; ANTIDEPRESSANT AGENT; BACLOFEN; CARRIER PROTEIN; DOPAMINE TRANSPORTER; G PROTEIN COUPLED RECEPTOR; GLYCINE TRANSPORTER 1; HOMOTAURINE; LAT PROTEIN; METFORMIN; METHYLPHENIDATE; NORADRENALIN TRANSPORTER; SEROTONIN TRANSPORTER; SOLUTE CARRIER TRANSPORTER; TALSACLIDINE; UNCLASSIFIED DRUG; VESICULAR AMINE TRANSPORTER; VESICULAR GLUTAMATE TRANSPORTER;

ALZHEIMER DISEASE; BINDING SITE; CLUSTER ANALYSIS; CYTOTOXICITY; DIARRHEA; DRUG METABOLISM; GENE MUTATION; GENETIC VARIABILITY; HEART PALPITATION; HIGH THROUGHPUT SCREENING; HUMAN; HYPERTENSION; LIPOPHILICITY; MOLECULAR DOCKING; MOLECULAR DYNAMICS; MOLECULAR MODEL; NAUSEA; NONHUMAN; PHARMACODYNAMICS; PREDICTION; PROTEIN CONFORMATION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; SEQUENCE ANALYSIS; SIDE EFFECT; SWEATING; TACHYCARDIA; VALIDATION PROCESS; X RAY ANALYSIS;

EID: 84878781602     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026611313070007     Document Type: Review

References (161)

1. Hediger, M.A.; Romero, M.F.; Peng, J.B.; Rolfs, A.; Takanaga, H.; Bruford, E.A., The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction. Pflugers Arch., 2004, 447(5), 465-468.
2. Povey, S.; Lovering, R.; Bruford, E.; Wright, M.; Lush, M.; Wain, H., The HUGO Gene Nomenclature Committee (HGNC). Hum. Genet., 2001, 109(6), 678-680.
3. Saier, M.H., A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol. Mol. Biol. Rev., 2000, 64(2), 354-411.
4. Saier, M.H. Yen, M.R.; Noto, K.; Tamang, D.G.; Elkan, C., The Transporter Classification Database: recent advances. Nucleic Acids Res., 2009, 37(Database issue), D274-278.
5. Forrest, L.R.; Rudnick, G., The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters. Physiology (Bethesda), 2009, 24, 377-386.
6. Forrest, L.R.; Kramer, R.; Ziegler, C., The structural basis of secondary active transport mechanisms. Biochim. Biophys. Acta, 2011, 1807(2), 167-188.
7. Jardetzky, O., Simple allosteric model for membrane pumps. Nature, 1966, 211(5052), 969-970.
8. Gether, U.; Andersen, P.H.; Larsson, O.M.; Schousboe, A., Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol. Sci., 2006, 27(7), 375-383.
9. Blakely, R.D.; DeFelice, L.J., All aglow about presynaptic receptor regulation of neurotransmitter transporters. Mol. Pharmacol., 2007, 71(5), 1206-1208.
10. Chen, N.H.; Reith, M.E.; Quick, M.W., Synaptic uptake and beyond: the sodium-and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch., 2004, 447(5), 519-531.
11. You, G., Morris, M. E., Wang, B. Drug Transporters: Molecular Characterization and Role in Drug Disposition. Wiley: Hoboken, 2007.
12. Otsuka, M.; Matsumoto, T.; Morimoto, R.; Arioka, S.; Omote, H.; Moriyama, Y., A human transporter protein that mediates the final excretion step for toxic organic cations. Proc. Natl. Acad. Sci. U. S. A., 2005, 102(50), 17923-17928.
13. Meyer zu Schwabedissen, H.E.; Verstuyft, C.; Kroemer, H.K.; Becquemont, L.; Kim, R.B., Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am. J. Physiol. Renal Physiol., 2010, 298(4), F997-F1005.
14. Leabman, M.K.; Huang, C.C.; DeYoung, J.; Carlson, E.J.; Taylor, T.R.; de la Cruz, M.; Johns, S.J.; Stryke, D.; Kawamoto, M.; Urban, T.J.; Kroetz, D.L.; Ferrin, T.E.; Clark, A.G.; Risch, N.; Herskowitz, I.; Giacomini, K.M., Natural variation in human membrane transporter genes reveals evolutionary and functional constraints. Proc. Natl. Acad. Sci. U. S. A., 2003, 100(10), 5896-5901.
15. Koepsell, H.; Schmitt, B.M.; Gorboulev, V., Organic cation transporters. Rev. Physiol. Biochem. Pharmacol., 2003, 150, 36-90.
16. Cropp, C.D.; Yee, S.W.; Giacomini, K.M., Genetic variation in drug transporters in ethnic populations. Clin. Pharmacol. Ther., 2008, 84(3), 412-416.
17. Giacomini, K.M.; Huang, S.M.; Tweedie, D.J.; Benet, L.Z.; Brouwer, K.L.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K.M.; Hoffmaster, K.A.; Ishikawa, T.; Keppler, D.; Kim, R.B.; Lee, C.A.; Niemi, M.; Polli, J.W.; Sugiyama, Y.; Swaan, P.W.; Ware, J.A.; Wright, S.H.; Yee, S.W.; Zamek-Gliszczynski, M.J.; Zhang, L., Membrane transporters in drug development. Nat. Rev. Drug Discov., 2010, 9(3), 215-236.
18. Shu, Y.; Brown, C.; Castro, R.A.; Shi, R.J.; Lin, E.T.; Owen, R.P.; Sheardown, S.A.; Yue, L.; Burchard, E.G.; Brett, C.M.; Giacomini, K.M., Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin. Pharmacol. Ther., 2008, 83(2), 273-280.
19. Shu, Y.; Sheardown, S.A.; Brown, C.; Owen, R.P.; Zhang, S.; Castro, R.A.; Ianculescu, A.G.; Yue, L.; Lo, J.C.; Burchard, E.G.; Brett, C.M.; Giacomini, K.M., Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J. Clin. Invest., 2007, 117(5), 1422-1431.
20. Shu, Y.; Leabman, M.K.; Feng, B.; Mangravite, L.M.; Huang, C.C.; Stryke, D.; Kawamoto, M.; Johns, S.J.; DeYoung, J.; Carlson, E.; Ferrin, T.E.; Herskowitz, I.; Giacomini, K.M., Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc. Natl. Acad. Sci. U. S. A., 2003, 100(10), 5902-5907.
21. Dresser, M.J.; Gray, A.T.; Giacomini, K.M., Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1). J. Pharmacol. Exp. Ther., 2000, 292(3), 1146-1152.
22. Fredriksson, R.; Nordstrom, K.J.; Stephansson, O.; Hagglund, M.G.; Schioth, H.B., The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families. FEBS Lett., 2008, 582(27), 3811-3816.
23. Gruswitz, F.; Chaudhary, S.; Ho, J.D.; Schlessinger, A.; Pezeshki, B.; Ho, C.M.; Sali, A.; Westhoff, C.M.; Stroud, R.M., Function of human Rh based on structure of RhCG at 2.1 A. Proc. Natl. Acad. Sci. U. S. A., 2010, 107(21), 9638-9643.
24. Karpowich, N.K.; Wang, D.N., Structural biology. Symmetric transporters for asymmetric transport. Science, 2008, 321(5890), 781-782.
25. Forrest, L.R.; Zhang, Y.W.; Jacobs, M.T.; Gesmonde, J.; Xie, L.; Honig, B.H.; Rudnick, G., Mechanism for alternating access in neurotransmitter transporters. Proc. Natl. Acad. Sci. U. S. A., 2008, 105(30), 10338-10343.
26. Gao, X.; Lu, F.; Zhou, L.; Dang, S.; Sun, L.; Li, X.; Wang, J.; Shi, Y., Structure and mechanism of an amino acid antiporter. Science, 2009, 324(5934), 1565-1568.
27. Fang, Y.; Jayaram, H.; Shane, T.; Kolmakova-Partensky, L.; Wu, F.; Williams, C.; Xiong, Y.; Miller, C., Structure of a prokaryotic virtual proton pump at 3.2 A resolution. Nature, 2009, 460(7258), 1040-1043.
28. Shaffer, P.L.; Goehring, A.; Shankaranarayanan, A.; Gouaux, E., Structure and mechanism of a na+-independent amino Acid transporter. Science, 2009, 325(5943), 1010-1014.
29. Lu, F.; Li, S.; Jiang, Y.; Jiang, J.; Fan, H.; Lu, G.; Deng, D.; Dang, S.; Zhang, X.; Wang, J.; Yan, N., Structure and mechanism of the uracil transporter UraA. Nature, 2011, 472(7342), 243-246.
30. Weyand, S.; Shimamura, T.; Yajima, S.; Suzuki, S.; Mirza, O.; Krusong, K.; Carpenter, E.P.; Rutherford, N.G.; Hadden, J.M.; O'Reilly, J.; Ma, P.; Saidijam, M.; Patching, S.G.; Hope, R.J.; Norbertczak, H.T.; Roach, P.C.; Iwata, S.; Henderson, P.J.; Cameron, A.D., Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter. Science, 2008, 322(5902), 709-713.
31. Ressl, S.; Terwisscha van Scheltinga, A.C.; Vonrhein, C.; Ott, V.; Ziegler, C., Molecular basis of transport and regulation in the Na(+)/betaine symporter BetP. Nature, 2009, 458(7234), 47-52.
32. Ma, D.; Lu, P.; Yan, C.; Fan, C.; Yin, P.; Wang, J.; Shi, Y., Structure and mechanism of a glutamate-GABA antiporter. Nature, 2012, 483(7391), 632-636.
33. Schulze, S.; Koster, S.; Geldmacher, U.; Terwisscha van Scheltinga, A.C.; Kuhlbrandt, W., Structural basis of Na(+)-independent and cooperative substrate/product antiport in CaiT. Nature, 2010, 467(7312), 233-236.
34. Lomize, M.A.; Lomize, A.L.; Pogozheva, I.D.; Mosberg, H.I., OPM: orientations of proteins in membranes database. Bioinformatics, 2006, 22(5), 623-625.
35. Krishnamurthy, H.; Piscitelli, C.L.; Gouaux, E., Unlocking the molecular secrets of sodium-coupled transporters. Nature, 2009, 459(7245), 347-355.
36. Abramson, J.; Wright, E.M., Structure and function of Na(+)-symporters with inverted repeats. Curr. Opin. Struct. Biol., 2009, 19(4), 425-432.
37. Khafizov, K.; Staritzbichler, R.; Stamm, M.; Forrest, L.R., A study of the evolution of inverted-topology repeats from LeuT-fold transporters using AlignMe. Biochemistry, 2010, 49(50), 10702-10713.
38. Kanner, B.I.; Zomot, E., Sodium-coupled neurotransmitter transporters. Chem. Rev., 2008, 108(5), 1654-1668.
39. Guan, L.; Kaback, H.R., Lessons from lactose permease. Annu. Rev. Biophys. Biomol. Struct., 2006, 35, 67-91.
40. Krishnamurthy, H.; Gouaux, E., X-ray structures of LeuT in substrate-free outward-open and apo inward-open states. Nature, 2012, 481(7382), 469-474.
41. Nyola, A.; Karpowich, N.K.; Zhen, J.; Marden, J.; Reith, M.E.; Wang, D.N., Substrate and drug binding sites in LeuT. Curr. Opin. Struct. Biol., 2010, 20(4), 415-422.
42. Singh, S.K.; Piscitelli, C.L.; Yamashita, A.; Gouaux, E., A competitive inhibitor traps LeuT in an open-to-out conformation. Science, 2008, 322(5908), 1655-1661.
43. Shi, L.; Quick, M.; Zhao, Y.; Weinstein, H.; Javitch, J.A., The mechanism of a neurotransmitter:sodium symporter--inward release of Na+ and substrate is triggered by substrate in a second binding site. Mol. Cell, 2008, 30(6), 667-677.
44. Zhao, Y.; Terry, D.; Shi, L.; Weinstein, H.; Blanchard, S.C.; Javitch, J.A., Single-molecule dynamics of gating in a neurotransmitter transporter homologue. Nature, 2010, 465(7295), 188-193.
45. Zhao, Y.; Terry, D.S.; Shi, L.; Quick, M.; Weinstein, H.; Blanchard, S.C.; Javitch, J.A., Substrate-modulated gating dynamics in a Na(+)-coupled neurotransmitter transporter homologue. Nature, 2011.
46. Claxton, D.P.; Quick, M.; Shi, L.; de Carvalho, F.D.; Weinstein, H.; Javitch, J.A.; McHaourab, H.S., Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters. Nat. Struct. Mol. Biol., 2010, 17(7), 822-829.
47. Shimamura, T.; Weyand, S.; Beckstein, O.; Rutherford, N.G.; Hadden, J.M.; Sharples, D.; Sansom, M.S.; Iwata, S.; Henderson, P.J.; Cameron, A.D., Molecular basis of alternating access membrane transport by the sodium-hydantoin transporter Mhp1. Science, 2010, 328(5977), 470-473.
48. Gao, X.; Zhou, L.; Jiao, X.; Lu, F.; Yan, C.; Zeng, X.; Wang, J.; Shi, Y., Mechanism of substrate recognition and transport by an amino acid antiporter. Nature, 2010, 463(7282), 828-832.
49. Radestock, S.; Forrest, L.R., The alternating-access mechanism of MFS transporters arises from inverted-topology repeats. J. Mol. Biol., 2011, 407(5), 698-715.
50. Faraldo-Gomez, J.D.; Forrest, L.R., Modeling and simulation of ion-coupled and ATP-driven membrane proteins. Curr. Opin. Struct. Biol., 2011, 21(2), 173-179.
51. Schlessinger, A.; Matsson, P.; Shima, J.E.; Pieper, U.; Yee, S.W.; Kelly, L.; Apeltsin, L.; Stroud, R.M.; Ferrin, T.E.; Giacomini, K.M.; Sali, A., Comparison of human solute carriers. Protein Sci., 2010, 19(3), 412-428.
52. Rost, B.; Liu, J.; Nair, R.; Wrzeszczynski, K.O.; Ofran, Y., Automatic prediction of protein function. Cell. Mol. Life Sci., 2003, 60(12), 2637-2650.
53. Sun, L.; Zeng, X.; Yan, C.; Sun, X.; Gong, X.; Rao, Y.; Yan, N., Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature, 2012, 490(7420), 361-366.
54. Abramson, J.; Smirnova, I.; Kasho, V.; Verner, G.; Kaback, H.R.; Iwata, S., Structure and mechanism of the lactose permease of Escherichia coli. Science, 2003, 301(5633), 610-615.
55. Newstead, S.; Drew, D.; Cameron, A.D.; Postis, V.L.; Xia, X.; Fowler, P.W.; Ingram, J.C.; Carpenter, E.P.; Sansom, M.S.; McPherson, M.J.; Baldwin, S.A.; Iwata, S., Crystal structure of a prokaryotic homologue of the mammalian oligopeptide-proton symporters, PepT1 and PepT2. EMBO J., 2011, 30(2), 417-426.
56. Kernytsky, A.; Rost, B., Static benchmarking of membrane helix predictions. Nucleic Acids Res., 2003, 31(13), 3642-3644.
57. Elofsson, A.; von Heijne, G., Membrane protein structure: prediction versus reality. Annu. Rev. Biochem., 2007, 76, 125-140.
58. Punta, M.; Forrest, L.R.; Bigelow, H.; Kernytsky, A.; Liu, J.; Rost, B., Membrane protein prediction methods. Methods, 2007, 41(4), 460-474.
59. Nugent, T.; Jones, D.T., Membrane protein structural bioinformatics. J. Struct. Biol., 2012, 179(3), 327-337.
60. Nugent, T.; Jones, D.T., Transmembrane protein topology prediction using support vector machines. BMC Bioinformatics, 2009, 10, 159.
61. Soding, J.; Biegert, A.; Lupas, A.N., The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res., 2005, 33(Web Server issue), W244-248.
62. Pei, J.; Kim, B.H.; Grishin, N.V., PROMALS3D: a tool for multiple protein sequence and structure alignments. Nucleic Acids Res., 2008, 36(7), 2295-2300.
63. Albers, T.; Marsiglia, W.; Thomas, T.; Gameiro, A.; Grewer, C., Defining substrate and blocker activity of alanine-serine-cysteine transporter 2 (ASCT2) Ligands with Novel Serine Analogs. Mol. Pharmacol., 2012, 81(3), 356-365.
64. Beuming, T.; Shi, L.; Javitch, J.A.; Weinstein, H., A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function. Mol. Pharmacol., 2006, 70(5), 1630-1642.
65. Atkinson, H.J.; Morris, J.H.; Ferrin, T.E.; Babbitt, P.C., Using sequence similarity networks for visualization of relationships across diverse protein superfamilies. PLoS One, 2009, 4(2), e4345.
66. Brown, S.D.; Babbitt, P.C., Inference of functional properties from large-scale analysis of enzyme superfamilies. J. Biol. Chem., 2012, 287(1), 35-42.
67. Marti-Renom, M.A.; Stuart, A.C.; Fiser, A.; Sanchez, R.; Melo, F.; Sali, A., Comparative protein structure modeling of genes and genomes. Annu. Rev. Biophys. Biomol. Struct., 2000, 29, 291-325.
68. Petrey, D.; Honig, B., Protein structure prediction: inroads to biology. Mol. Cell, 2005, 20(6), 811-819.
69. Schmidt, T.; Haas, J.; Gallo Cassarino, T.; Schwede, T., Assessment of ligand-binding residue predictions in CASP9. Proteins, 2011, 79 Suppl 10, 126-136.
70. Larsson, P.; Wallner, B.; Lindahl, E.; Elofsson, A., Using multiple templates to improve quality of homology models in automated homology modeling. Protein Sci., 2008, 17(6), 990-1002.
71. Ginalski, K., Comparative modeling for protein structure prediction. Curr. Opin. Struct. Biol., 2006, 16(2), 172-177.
72. Fiser, A., Template-based protein structure modelling. Methods Mol. Biol., 2010, 673, 73-94.
73. Sali, A.; Blundell, T.L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol., 1993, 234(3), 779-815.
74. Eramian, D.; Eswar, N.; Shen, M.Y.; Sali, A., How well can the accuracy of comparative protein structure models be predicted? Protein Sci., 2008, 17(11), 1881-1893.
75. Eramian, D.; Shen, M.Y.; Devos, D.; Melo, F.; Sali, A.; Marti-Renom, M.A., A composite score for predicting errors in protein structure models. Protein Sci., 2006, 15(7), 1653-1666.
76. Schwede, T.; Sali, A.; Honig, B.; Levitt, M.; Berman, H.M.; Jones, D.; Brenner, S.E.; Burley, S.K.; Das, R.; Dokholyan, N.V.; Dunbrack, R.L., Jr.; Fidelis, K.; Fiser, A.; Godzik, A.; Huang, Y.J.; Humblet, C.; Jacobson, M.P.; Joachimiak, A.; Krystek, S.R., Jr.; Kortemme, T.; Kryshtafovych, A.; Montelione, G.T.; Moult, J.; Murray, D.; Sanchez, R.; Sosnick, T.R.; Standley, D.M.; Stouch, T.; Vajda, S.; Vasquez, M.; Westbrook, J.D.; Wilson, I.A., Outcome of a workshop on applications of protein models in biomedical research. Structure, 2009, 17(2), 151-159.
77. Wallner, B.; Elofsson, A., All are not equal: a benchmark of different homology modeling programs. Protein Sci., 2005, 14(5), 1315-1327.
78. Fasnacht, M.; Zhu, J.; Honig, B., Local quality assessment in homology models using statistical potentials and support vector machines. Protein Sci., 2007, 16(8), 1557-1568.
79. Shoichet, B.K.; McGovern, S.L.; Wei, B.; Irwin, J.J., Lead discovery using molecular docking. Curr. Opin. Chem. Biol., 2002, 6(4), 439-446.
80. Shoichet, B.K., Virtual screening of chemical libraries. Nature, 2004, 432(7019), 862-865.
81. Jacobson, M.; Sali, A. In Annual Reports in Medicinal Chemistry; Academic Press, 2004; Vol. Volume 39, pp 259-276.
82. Shoichet, B.K.; Stroud, R.M.; Santi, D.V.; Kuntz, I.D.; Perry, K.M., Structure-based discovery of inhibitors of thymidylate synthase. Science, 1993, 259(5100), 1445-1450.
83. Mysinger, M.M.; Shoichet, B.K., Rapid context-dependent ligand desolvation in molecular docking. J. Chem. Inf. Model., 2010, 50(9), 1561-1573.
84. Kuntz, I.D., Structure-based strategies for drug design and discovery. Science, 1992, 257(5073), 1078-1082.
85. Huang, N.; Shoichet, B.K.; Irwin, J.J., Benchmarking sets for molecular docking. J. Med. Chem., 2006, 49(23), 6789-6801.
86. Fan, H.; Irwin, J.J.; Webb, B.M.; Klebe, G.; Shoichet, B.K.; Sali, A., Molecular docking screens using comparative models of proteins. J. Chem. Inf. Model., 2009, 49(11), 2512-2527.
87. Schlessinger, A.; Geier, E.; Fan, H.; Irwin, J.J.; Shoichet, B.K.; Giacomini, K.M.; Sali, A., Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET. Proc. Natl. Acad. Sci. U. S. A., 2011, 108(38), 15810-15815.
88. Evers, A.; Gohlke, H.; Klebe, G., Ligand-supported homology modelling of protein binding-sites using knowledge-based potentials. J. Mol. Biol., 2003, 334(2), 327-345.
89. Cavasotto, C.N.; Orry, A.J.; Murgolo, N.J.; Czarniecki, M.F.; Kocsi, S.A.; Hawes, B.E.; O'Neill, K.A.; Hine, H.; Burton, M.S.; Voigt, J.H.; Abagyan, R.A.; Bayne, M.L.; Monsma, F.J., Jr., Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening. J. Med. Chem., 2008, 51(3), 581-588.
90. Carlsson, J.; Coleman, R.G.; Setola, V.; Irwin, J.J.; Fan, H.; Schlessinger, A.; Sali, A.; Roth, B.L.; Shoichet, B.K., Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat. Chem. Biol., 2011, 7(11), 769-778.
91. Schlessinger, A.; Wittwer, M.B.; Dahlin, A.; Khuri, N.; Bonomi, M.; Fan, H.; Giacomini, K.M.; Sali, A., High Selectivity of the gamma-Aminobutyric Acid Transporter 2 (GAT-2, SLC6A13) Revealed by Structure-based Approach. J. Biol. Chem., 2012, 287(45), 37745-37756.
92. Shoichet, B.K.; Kobilka, B.K., Structure-based drug screening for G-protein-coupled receptors. Trends Pharmacol. Sci., 2012, 33(5), 268-272.
93. Kufareva, I.; Rueda, M.; Katritch, V.; Stevens, R.C.; Abagyan, R., Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. Structure, 2011, 19(8), 1108-1126.
94. Schapira, M.; Abagyan, R.; Totrov, M., Nuclear hormone receptor targeted virtual screening. J. Med. Chem., 2003, 46(14), 3045-3059.
95. Diller, D.J.; Li, R., Kinases, homology models, and high throughput docking. J. Med. Chem., 2003, 46(22), 4638-4647.
96. Song, L.; Kalyanaraman, C.; Fedorov, A.A.; Fedorov, E.V.; Glasner, M.E.; Brown, S.; Imker, H.J.; Babbitt, P.C.; Almo, S.C.; Jacobson, M.P.; Gerlt, J.A., Prediction and assignment of function for a divergent N-succinyl amino acid racemase. Nat. Chem. Biol., 2007, 3(8), 486-491.
97. Kalyanaraman, C.; Imker, H.J.; Fedorov, A.A.; Fedorov, E.V.; Glasner, M.E.; Babbitt, P.C.; Almo, S.C.; Gerlt, J.A.; Jacobson, M.P., Discovery of a dipeptide epimerase enzymatic function guided by homology modeling and virtual screening. Structure, 2008, 16(11), 1668-1677.
98. Astorga, B.; Ekins, S.; Morales, M.; Wright, S.H., Molecular determinants of ligand selectivity for the human multidrug and toxin extruder proteins MATE1 and MATE2-K. J. Pharmacol. Exp. Ther., 2012, 341(3), 743-755.
99. Andersen, J.; Kristensen, A.S.; Bang-Andersen, B.; Stromgaard, K., Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters. Chem. Commun. (Camb.), 2009(25), 3677-3692.
100. Ekins, S.; Ecker, G.F.; Chiba, P.; Swaan, P.W., Future directions for drug transporter modelling. Xenobiotica, 2007, 37(10-11), 1152-1170.
101. Chang, C.; Swaan, P.W., Computational approaches to modeling drug transporters. Eur. J. Pharm. Sci., 2006, 27(5), 411-424.
102. Eyre, T.A.; Partridge, L.; Thornton, J.M., Computational analysis of alpha-helical membrane protein structure: implications for the prediction of 3D structural models. Protein Eng. Des. Sel., 2004, 17(8), 613-624.
103. Hahn, M.K.; Blakely, R.D., The functional impact of SLC6 transporter genetic variation. Annu. Rev. Pharmacol. Toxicol., 2007, 47, 401-441.
104. Pacholczyk, T.; Blakely, R.D.; Amara, S.G., Expression cloning of a cocaine-and antidepressant-sensitive human noradrenaline transporter. Nature, 1991, 350(6316), 350-354.
105. Celik, L.; Sinning, S.; Severinsen, K.; Hansen, C.G.; Moller, M.S.; Bols, M.; Wiborg, O.; Schiott, B., Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation. J. Am. Chem. Soc., 2008, 130(12), 3853-3865.
106. Beuming, T.; Kniazeff, J.; Bergmann, M.L.; Shi, L.; Gracia, L.; Raniszewska, K.; Newman, A.H.; Javitch, J.A.; Weinstein, H.; Gether, U.; Loland, C.J., The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat. Neurosci., 2008,11(7), 780-789.
107. Severinsen, K.; Kraft, J.F.; Koldso, H.; Vinberg, K.A.; Rothman, R.B.; Partilla, J.S.; Wiborg, O.; Blough, B.; Schiott, B.; Sinning, S., Binding of the Amphetamine-like 1-Phenyl-piperazine to Monoamine Transporters. ACS Chem. Neurosci., 2012, 3(9), 693-705.
108. Daylight Chemical Information Systems, Inc., Laguna Niguel, CA 92677.
109. Adamus, W.S.; Leonard, J.P.; Troger, W., Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer's disease. Life Sci., 1995, 56(11-12), 883-890.
110. Madsen, K.K.; White, H.S.; Schousboe, A., Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol. Ther., 2010, 125(3), 394-401.
111. Christiansen, B.; Meinild, A.K.; Jensen, A.A.; Brauner-Osborne, H., Cloning and characterization of a functional human gamma-aminobutyric acid (GABA) transporter, human GAT-2. J. Biol. Chem., 2007, 282(27), 19331-19341.
112. Nakashita, M.; Sasaki, K.; Sakai, N.; Saito, N., Effects of tricyclic and tetracyclic antidepressants on the three subtypes of GABA transporter. Neurosci. Res., 1997, 29(1), 87-91.
113. Melamed, N.; Kanner, B.I., Transmembrane domains I and II of the gamma-aminobutyric acid transporter GAT-4 contain molecular determinants of substrate specificity. Mol. Pharmacol., 2004, 65(6), 1452-1461.
114. Kanner, B.I., Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes. J. Biol. Chem., 2003, 278(6), 3705-3712.
115. Irwin, J.J.; Shoichet, B.K., ZINC--a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model., 2005, 45(1), 177-182.
116. Albers, J.W.; Fink, J.K., Porphyric neuropathy. Muscle Nerve, 2004,30(4), 410-422.
117. Lindberg, R.L.; Martini, R.; Baumgartner, M.; Erne, B.; Borg, J.; Zielasek, J.; Ricker, K.; Steck, A.; Toyka, K.V.; Meyer, U.A., Motor neuropathy in porphobilinogen deaminase-deficient mice imitates the peripheral neuropathy of human acute porphyria. J. Clin. Invest., 1999, 103(8), 1127-1134.
118. Musiol, R.; Serda, M.; Polanski, J., Prodrugs in photodynamic anticancer therapy. Curr. Pharm. Des., 2011, 17(32), 3548-3559.
119. Stummer, W.; Pichlmeier, U.; Meinel, T.; Wiestler, O.D.; Zanella, F.; Reulen, H.J., Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol., 2006,7(5), 392-401.
120. Fukuda, H.; Casas, A.; Batlle, A., Aminolevulinic acid: from its unique biological function to its star role in photodynamic therapy. Int. J. Biochem. Cell Biol., 2005, 37(2), 272-276.
121. Kanai, Y.; Segawa, H.; Miyamoto, K.; Uchino, H.; Takeda, E.; Endou, H., Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem., 1998, 273(37), 23629-23632.
122. Roberts, L.M.; Black, D.S.; Raman, C.; Woodford, K.; Zhou, M.; Haggerty, J.E.; Yan, A.T.; Cwirla, S.E.; Grindstaff, K.K., Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation. Neuroscience, 2008, 155(2), 423-438.
123. Alexander, G.M.; Schwartzman, R.J.; Grothusen, J.R.; Gordon, S.W., Effect of plasma levels of large neutral amino acids and degree of parkinsonism on the blood-to-brain transport of levodopa in naive and MPTP parkinsonian monkeys. Neurology, 1994, 44(8), 1491-1499.
124. Wang, Y.; Welty, D.F., The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm. Res., 1996, 13(3), 398-403.
125. Kaira, K.; Oriuchi, N.; Imai, H.; Shimizu, K.; Yanagitani, N.; Sunaga, N.; Hisada, T.; Tanaka, S.; Ishizuka, T.; Kanai, Y.; Endou, H.; Nakajima, T.; Mori, M., Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br. J. Cancer, 2008, 98(4), 742-748.
126. Kobayashi, K.; Ohnishi, A.; Promsuk, J.; Shimizu, S.; Kanai, Y.; Shiokawa, Y.; Nagane, M., Enhanced tumor growth elicited by L-type amino acid transporter 1 in human malignant glioma cells. Neurosurgery, 2008, 62(2), 493-503; discussion 503-494.
127. Kroemer, G.; Pouyssegur, J., Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell, 2008, 13(6), 472-482.
128. Nicklin, P.; Bergman, P.; Zhang, B.; Triantafellow, E.; Wang, H.; Nyfeler, B.; Yang, H.; Hild, M.; Kung, C.; Wilson, C.; Myer, V.E.; MacKeigan, J.P.; Porter, J.A.; Wang, Y.K.; Cantley, L.C.; Finan, P.M.; Murphy, L.O., Bidirectional transport of amino acids regulates mTOR and autophagy. Cell, 2009, 136(3), 521-534.
129. Verrey, F.; Closs, E.I.; Wagner, C.A.; Palacin, M.; Endou, H.; Kanai, Y., CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch., 2004, 447(5), 532-542.
130. Geier, E.G.; Schlessinger, A.; Fan, H.; Gable, J.E.; Irwin, J.J.; Sali, A.; Giacomini, K.M., Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1. Proc. Natl. Acad. Sci. U. S. A., 2013, 110(14), 5480-5485.
131. Hidalgo, M.; Rodriguez, G.; Kuhn, J.G.; Brown, T.; Weiss, G.; MacGovren, J.P.; Von Hoff, D.D.; Rowinsky, E.K., A Phase I and pharmacological study of the glutamine antagonist acivicin with the amino acid solution aminosyn in patients with advanced solid malignancies. Clin. Cancer Res., 1998, 4(11), 2763-2770.
132. Dolghih, E.; Bryant, C.; Renslo, A.R.; Jacobson, M.P., Predicting binding to p-glycoprotein by flexible receptor docking. PLoS Comput. Biol., 2011, 7(6), e1002083.
133. Masuda, S.; Terada, T.; Yonezawa, A.; Tanihara, Y.; Kishimoto, K.; Katsura, T.; Ogawa, O.; Inui, K., Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J. Am. Soc. Nephrol., 2006, 17(8), 2127-2135.
134. Otsuka, M.; Yasuda, M.; Morita, Y.; Otsuka, C.; Tsuchiya, T.; Omote, H.; Moriyama, Y., Identification of essential amino acid residues of the NorM Na+/multidrug antiporter in Vibrio parahaemolyticus. J. Bacteriol., 2005, 187(5), 1552-1558.
135. Becker, M.L.; Visser, L.E.; van Schaik, R.H.; Hofman, A.; Uitterlinden, A.G.; Stricker, B.H., Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenomics J., 2009, 9(4), 242-247.
136. Jablonski, K.A.; McAteer, J.B.; de Bakker, P.I.; Franks, P.W.; Pollin, T.I.; Hanson, R.L.; Saxena, R.; Fowler, S.; Shuldiner, A.R.; Knowler, W.C.; Altshuler, D.; Florez, J.C., Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes, 2010, 59(10), 2672-2681.
137. Nies, A.T.; Koepsell, H.; Damme, K.; Schwab, M., Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb. Exp. Pharmacol., 2011(201), 105-167.
138. Damme, K.; Nies, A.T.; Schaeffeler, E.; Schwab, M., Mammalian MATE (SLC47A) transport proteins: impact on efflux of endogenous substrates and xenobiotics. Drug Metab. Rev., 2011, 43(4), 499-523.
139. Kido, Y.; Matsson, P.; Giacomini, K.M., Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J. Med. Chem., 2011, 54(13), 4548-4558.
140. Wittwer, M.B.; Zur, A.A.; Khuri, N.; Kido, Y.; Kosaka, A.; Zhang, X.; Morrissey, K.M.; Sali, A.; Huang, Y.; Giacomini, K.M., Discovery of Potent, Selective Multidrug and Toxin Extrusion Transporter 1 (MATE1, SLC47A1) Inhibitors Through Prescription Drug Profiling and Computational Modeling. J. Med. Chem., 2013.
141. Wishart, D.S.; Knox, C.; Guo, A.C.; Shrivastava, S.; Hassanali, M.; Stothard, P.; Chang, Z.; Woolsey, J., DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res., 2006, 34(Database issue), D668-672.
142. He, X.; Szewczyk, P.; Karyakin, A.; Evin, M.; Hong, W.X.; Zhang, Q.; Chang, G., Structure of a cation-bound multidrug and toxic compound extrusion transporter. Nature, 2010, 467(7318), 991-994.
143. Zhang, X.; Wright, S.H., MATE1 has an external COOH terminus, consistent with a 13-helix topology. Am. J. Physiol. Renal Physiol., 2009, 297(2), F263-271.
144. Zhang, X.; He, X.; Baker, J.; Tama, F.; Chang, G.; Wright, S.H., Twelve transmembrane helices form the functional core of mammalian MATE1 (multidrug and toxin extruder 1) protein. J. Biol. Chem., 2012, 287(33), 27971-27982.
145. Kajiwara, M.; Terada, T.; Ogasawara, K.; Iwano, J.; Katsura, T.; Fukatsu, A.; Doi, T.; Inui, K., Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity. J. Hum. Genet., 2009, 54(1), 40-46.
146. Choi, J.H.; Yee, S.W.; Ramirez, A.H.; Morrissey, K.M.; Jang, G.H.; Joski, P.J.; Mefford, J.A.; Hesselson, S.E.; Schlessinger, A.; Jenkins, G.; Castro, R.A.; Johns, S.J.; Stryke, D.; Sali, A.; Ferrin, T.E.; Witte, J.S.; Kwok, P.Y.; Roden, D.M.; Wilke, R.A.; McCarty, C.A.; Davis, R.L.; Giacomini, K.M., A common 5'-UTR variant in MATE2-K is associated with poor response to metformin. Clin. Pharmacol. Ther., 2011, 90(5), 674-684.
147. Stroud, R.M.; Choe, S.; Holton, J.; Kaback, H.R.; Kwiatkowski, W.; Minor, D.L.; Riek, R.; Sali, A.; Stahlberg, H.; Harries, W., 2007 Annual progress report synopsis of the Center for Structures of Membrane Proteins. J. Struct. Funct. Genomics, 2009.
148. Love, J.; Mancia, F.; Shapiro, L.; Punta, M.; Rost, B.; Girvin, M.; Wang, D.N.; Zhou, M.; Hunt, J.F.; Szyperski, T.; Gouaux, E.; MacKinnon, R.; McDermott, A.; Honig, B.; Inouye, M.; Montelione, G.; Hendrickson, W.A., The New York Consortium on Membrane Protein Structure (NYCOMPS): a high-throughput platform for structural genomics of integral membrane proteins. J. Struct. Funct. Genomics, 2010, 11(3), 191-199.
149. Pieper, U.; Schlessinger, A.; Kloppmann, E.; Chang, G.A.; Chou, J.J.; Dumont, M.E.; Fox, B.G.; Fromme, P.; Hendrickson, W.A.; Malkowski, M.G.; Rees, D.C.; Stokes, D.L.; Stowell, M.H.; Wiener, M.C.; Rost, B.; Stroud, R.M.; Stevens, R.C.; Sali, A., Coordinating the impact of structural genomics on the human alpha-helical transmembrane proteome. Biology Nat. Struct. Mol. Biol., 2013, 20(2), 135-138.
150. Mysinger, M.M.; Weiss, D.R.; Ziarek, J.J.; Gravel, S.; Doak, A.K.; Karpiak, J.; Heveker, N.; Shoichet, B.K.; Volkman, B.F., Structure-based ligand discovery for the protein-protein interface of chemokine receptor CXCR4. Proc. Natl. Acad. Sci. U. S. A., 2012, 109(14), 5517-5522.
151. Fan, H.; Schneidman-Duhovny, D.; Irwin, J.J.; Dong, G.; Shoichet, B.K.; Sali, A., Statistical potential for modeling and ranking of protein-ligand interactions. J. Chem. Inf. Model., 2011, 51(12), 3078-3092.
152. Zamek-Gliszczynski, M.J.; Hoffmaster, K.A.; Tweedie, D.J.; Giacomini, K.M.; Hillgren, K.M., Highlights from the international transporter consortium second workshop. Clin. Pharmacol. Ther., 2012, 92(5), 553-556.
153. Boudker, O.; Ryan, R.M.; Yernool, D.; Shimamoto, K.; Gouaux, E., Coupling substrate and ion binding to extracellular gate of a sodium-dependent aspartate transporter. Nature, 2007, 445(7126), 387-393.
154. Yamashita, A.; Singh, S.K.; Kawate, T.; Jin, Y.; Gouaux, E., Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters. Nature, 2005, 437(7056), 215-223.
155. Hu, N.J.; Iwata, S.; Cameron, A.D.; Drew, D., Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature, 2011, 478(7369), 408-411.
156. Pebay-Peyroula, E.; Dahout-Gonzalez, C.; Kahn, R.; Trezeguet, V.; Lauquin, G.J.; Brandolin, G., Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature, 2003, 426(6962), 39-44.
157. Johnson, Z.L.; Cheong, C.G.; Lee, S.Y., Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4 A. Nature, 2012, 483(7390), 489-493.
158. DeLano, W.L. The PyMOL Molecular Graphics System, San Carlos, CA, USA, 2002.
159. Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T., Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
160. Madhusudhan, M.S.; Webb, B.M.; Marti-Renom, M.A.; Eswar, N.; Sali, A., Alignment of multiple protein structures based on sequence and structure features. Protein Eng. Des. Sel., 2009, 22(9), 569-574.
161. Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E., UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.