Robust ligand-based modeling of the biological targets of known drugs

Journal of Medicinal Chemistry

Volumn 49, Issue 10, 2006, Pages 2921-2938

  Cleves, Ann E ^a   Jain, Ajay N ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMOXICILLIN; BROMPHENIRAMINE; CYTOCHROME P450; DANAZOL; DIENESTROL; DIHYDROPTEROATE SYNTHASE; DIPEPTIDYL CARBOXYPEPTIDASE; DNA TOPOISOMERASE (ATP HYDROLYSING); G PROTEIN COUPLED RECEPTOR; HYOSCYAMINE; KETOCONAZOLE; LAMIVUDINE; LEVOFLOXACIN; LIDOCAINE; LIGAND; METOLAZONE; MIDAZOLAM; NIFEDIPINE; OXYCODONE; PARACETAMOL; PHENOBARBITAL; PRALIDOXIME; PREDNISONE; PROGESTERONE; RNA DIRECTED DNA POLYMERASE; SULFABENZAMIDE; TIMOLOL; TOLAZAMIDE; TRANDOLAPRIL; UNINDEXED DRUG;

ALGORITHM; ARTICLE; COMPUTER PROGRAM; CORRELATION COEFFICIENT; DRUG METABOLISM; DRUG SPECIFICITY; DRUG STRUCTURE; DRUG TARGETING; DRUG TRANSPORT; MOLECULAR IMPRINTING; MOLECULAR MODEL; QUANTITATIVE ANALYSIS; ROC CURVE; VIRTUAL REALITY;

COMPUTER SIMULATION; DRUG DESIGN; DRUG INTERACTIONS; LIGANDS; MODELS, MOLECULAR; PHARMACEUTICAL PREPARATIONS; PROTEINS; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33646730764     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm051139t     Document Type: Article

References (94)

1. Walters, P. W.; Stahl, M. T.; Murcko, M. A. Virtual screening-An overview. Drug Discovery Today 1998, 3, 160-178.
2. Jain, A. N. Virtual screening in lead discovery and optimization. Curr Opin. Drug. Discovery Dev. 2004, 7, 396-403.
3. Jain, A. N. Surflex: Fully automatic flexible molecular docking using a molecular similarity-based search engine. J. Med. Chem. 2003, 46, 499-511.
4. Pham, T. A.; Jain, A. N. Parameter estimation for scoring protein-ligand interactions using negative training data. J. Med. Chem. 2006, in press.
5. Kellenberger, E.; Rodrigo, J.; Muller, P.; Rognan, D. Comparative evaluation of eight docking tools for docking and virtual screening accuracy. Proteins 2004, 57, 225-242.
6. Miteva, M. A.; Lee, W. H.; Montes, M. O.; Villoutreix, B. O. Fast structure-based virtual ligand screening combining FRED, DOCK, and Surflex. J. Med. Chem. 2005, 48, 6012-6022.
7. Bissantz, C.; Folkers, G.; Rognan, D. Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. J. Med. Chem. 2000, 43, 4759-4767.
8. Bursulaya, B. D.; Totrov, M.; Abagyan, R.; Brooks, C. L., 3rd. Comparative study of several algorithms for flexible ligand docking. J Comput. Aided Mol. Des. 2003, 17, 755-763.
9. Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 2004, 47, 1750-1759.
10. Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 2004, 47, 1739-1749.
11. Nissink, J. W.; Murray, C.; Hartshorn, M.; Verdonk, M. L.; Cole, J. C.; Taylor, R. A new test set for validating predictions of protein-ligand interaction. Proteins 2002, 49, 457-471.
12. Verdonk, M. L.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Taylor, R. D. Improved protein-ligand docking using GOLD. Proteins 2003, 52, 609-623.
13. Jain, A. N.; Dietterich, T. G.; Lathrop, R. H.; Chapman, D.; Critchlow, R. E., Jr.; Bauer, B. E.; Webster, T. A.; Lozano-Perez, T. A shape-based machine learning tool for drug design. J. Comput. Aided. Mol. Des. 1994, 8, 635-652.
14. Jain, A. N.; Koile, K.; Chapman, D. Compass: Predicting biological activities from molecular surface properties. Performance comparisons on a steroid benchmark. J. Med. Chem. 1994, 37, 2315-2327.
15. Jain, A. N.; Harris, N. L.; Park, J. Y. Quantitative binding site model generation: Compass applied to multiple chemotypes targeting the 5-HT1A receptor. J. Med. Chem. 1995, 38, 1295-1308.
16. Jain, A. N. Chemical analysis by morphological similarity. US patent 6,470,305, 2002.
17. Perkins, E.; Sun, D.; Nguyen, A.; Tulac, S.; Francesco, M.; Tavana, H.; Nguyen, H.; Tugendreich, S.; Barthmaier, P.; Couto, J.; Yeh, E.; Thode, S.; Jarnagin, K.; Jain, A. N.; Morgans, D.; Melese, T. Novel inhibitors of poly(ADP-ribose) polymerase/PARP1 and PARP2 identified using a cell-based screen in yeast. Cancer Res. 2001, 61, 4175-4183.
18. Jain, A. N. Ligand-based structural hypotheses for virtual screening. J. Med. Chem. 2004, 47, 947-961.
19. Jain, A. N. Morphological similarity: A 3D molecular similarity method correlated with protein-ligand recognition. J. Comput. Aided Mol. Des. 2000, 14, 199-213.
20. Cramer, R. D.; Patterson, D. E.; Bunce, J. D. Comparative MOLECULAR FIELD Analysis (CoMFA). Effect of shape on binding of steroid to carrier proteins. J. Am. Chem. Soc. 1988, 110, 5959-5967.
21. Cramer, R. D. Topomer CoMFA: A design methodology for rapid lead optimization. J. Med. Chem. 2003. 46, 374-388.
22. Pitman, M. C.; Huber, W. K.; Horn, H.; Kramer, A.; Rice, J. E.; Swope, W. C. FLASHFLOOD: A 3D field-based similarity search and alignment method for flexible molecules. J. Comput. Aided Mol. Des. 2001, 15, 587-612.
23. Kramer, A.; Horn, H. W.; Rice, J. E. Fast 3D molecular superposition and similarity search in databases of flexible molecules. J. Comput. Aided Mol. Des. 2003, 17, 13-38.
24. Klebe, G.; Abraham, U. Comparative molecular similarity index analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries. J. Comput. Aided Mol. Des. 1999, 13, 1-10.
25. Klebe, G.; Mietzner, T.; Weber, F. Methodological developments and strategies for a fast flexible superposition of drug-size molecules. J. Comput. Aided Mol. Des. 1999, 13, 35-49.
26. Lemmen, C.; Lengauer, T.; Klebe, G. FLEXS: A method for fast flexible ligand superposition. J. Med. Chem. 1998, 41, 4502-4520.
27. Nicholls, A.; MacCuish, N. E.; MacCuish, J. D. Variable selection and model validation of 2D and 3D molecular descriptors. J. Comput. Aided Mol. Des. 2004, 18, 451-474.
28. Mestres, J.; Rohrer, D. C.; Maggiora, G. M. A molecular-field-based similarity study of non-nucleoside HIV-1 reverse transcriptase Inhibitors. 2. The relationship between alignment solutions obtained from conformationally rigid and flexible matching. J. Comput. Aided. Mol. Des. 2000, 14, 39-51.
29. Meurice, N.; Maggiora, G. M.; Vercauteren, D. P. Evaluating molecular similarity using reduced representations of the electron density. J. Mol. Model. (Online) 2005, 11, 237-247.
30. Renfrey, S.; Featherstone, J. Structural proteomics. Nat. Rev. Drug Discovery 2002, 1, 175-176.
31. Dmochowski, R.; Staskin, D. R. The q-T interval and antimuscarinic drugs. Curr. Urol. Rep. 2005, 6, 405-409.
32. Howell, G., 3rd; West, L.; Jenkins, C.; Lineberry, B.; Yokum, D.; Rockhold, R. In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine. BMC Pharmacol. 2005, 5, 13.
33. Fernandez, D.; Ghanta, A.; Kauffman, G. W.; Sanguinetti, M. C. Physicochemical features of the HERG channel drug binding site. J. Biol. Chem. 2004, 279, 10120-10127.
34. Daly, A. K. Pharmacogenetics of the cytochromes P450. Curr. Top. Med. Chem. 2004, 4, 1733-1744.
35. Sakaeda, T.; Nakamura, T.; Okumura, K. Pharmacogenetics of drug transporters and its impact on the pharmacotherapy. Curr. Top. Med. Chem. 2004, 4, 1385-1398.
36. Dresser, M. J.; Leabman, M. K.; Giacomini, K. M. Transporters involved in the elimination of drugs in the kidney: Organic anion transporters and organic cation transporters. J. Pharm. Sci. 2001, 90, 397-421.
37. Wu, C. Y.; Benet, L. Z. Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm. Res. 2005, 22, 11-23.
38. Mount, J.; Ruppert, J.; Welch, W.; Jain, A. N. IcePick: A flexible surface-based system for molecular diversity. J. Med. Chem. 1999, 42, 60-66.
39. Ghuloum, A. M.; Sage, C. R.; Jain, A. N. Molecular hashkeys: A novel method for molecular characterization and its application for predicting important pharmaceutical properties of molecules. J. Med. Chem. 1999, 42, 1739-1748.
40. Briem, H.; Kuntz, I. D. Molecular similarity based on DOCK-generated fingerprints. J. Med. Chem. 1996, 39, 3401-3408.
41. Kauvar, L. M.; Higgins, D. L.; Villar, H. O.; Sportsman, J. R.; Engqvist-Goldstein, A.; Bukar, R.; Bauer, K. E.; Dilley, H.; Rocke, D. M. Predicting ligand binding to proteins by affinity fingerprinting. Chem. Biol. 1995, 2, 107-118.
42. Maglott, D.; Ostell, J.; Pruitt, K. D.; Tatusova, T. Entrez Gene: Gene-centered information at NCBI. Nucleic Acids Res. 2005, 33, D54-58.
43. Sigel, E. Mapping of the benzodiazepine recognition site on GABA-(A) receptors. Curr. Top. Med. Chem. 2002, 2, 833-839.
44. Olshen, A. B.; Jain, A. N. Deriving quantitative conclusions from microarray expression data. Bioinformatics 2002, 18, 961-970.
45. Lacy, C. F.; Armstrong, L. L.; Goldman, M. P.; Lance, L. L. Drug Information Handbook, 13th ed.; Lexi-Comp: Hudson, OH, 2005.
46. Hardman, J. G.; Limbird, L. E.; Gilman, A. G. Goodman and Oilman's: The Pharmacological Basis of Therapeutics, 10th ed.; McGraw-Hill: New York, 2001.
47. Sonneveld, E.; Jansen, H. J.; Riteco, J. A.; Brouwer, A.; van der Burg, B. Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol. Sci. 2005, 83, 136-148.
48. Ragsdale, D. S.; McPhee, J. C.; Scheuer, T.; Catterall, W. A. Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 9270-9275.
49. Mullin, M. J.; Hunt, W. A. Ethanol inhibits veratridine-stimulated sodium uptake in synaptosomes. Life Sci. 1984, 34, 287-292.
50. Czapinski, P.; Blaszczyk, B.; Czuczwar, S. J. Mechanisms of action of antiepileptic drugs. Curr. Top. Med. Chem. 2005, 5, 3-14.
51. Frenkel, C.; Duch, D. S.; Recio-Pinto, E.; Urban, B. W. Pentobarbital suppresses human brain sodium channels. Brain Res. Mol. Brain Res. 1989, 6, 211-216.
52. Frenkel, C.; Duch, D. S.; Urban, B. W. Molecular actions of pentobarbital isomers on sodium channels from human brain cortex. Anesthesiology 1990, 72, 640-649.
53. Wartenberg, H. C.; Wartenberg, J. P.; Urban, B. W. Pharmacological modification of sodium channels from the human heart atrium in planar lipid bilayers: Electrophysiological characterization of responses to batrachotoxin and pentobarbital. Eur. J. Anaesthesiol. 2003, 20, 354-362.
54. O'Neil, M. J.; Smith, A.; Patricia, E. H.; Obenchain, J. R.; Gallipeau, J. A. R.; D'Arecca, M. A. Merck Index: An Encyclopedia of Chemicals, Drugs, & Biologicals, 13th ed.; Merck & Co.: Rahway, NJ. 2001.
55. DeLorey, T. M.; Olsen, R. W. Gamma-aminobutyric acidA receptor structure and function. J. Biol. Chem. 1992, 267, 16747-16750.
56. Rho, J. M.; Donevan, S. D.; Rogawski, M. A. Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate. J. Pharmacol. Exp. Ther. 1997, 280, 1383-1391.
57. Koe, B. K.; Minor, K. W.; Kondratas, T.; Lebel, L. A.; Koch, S. W. Enhancement of benzodiazepine binding by methaqualone and related quinazolines. Drug Dev. Res. 1986, 7, 255-268.
58. BeDell, L. S. Mosby's Complete Drug Reference; Mosby-Year Book, Inc.: St. Louis, 1997.
59. Gonzalez, M. A.; Estes, K. S. Pharmacokinetic overview of oral second-generation H1 antihistamines. Int. J. Clin. Pharmacol. Ther. 1998, 36, 292-300.
60. Kubo, N.; Shirakawa, O.; Kuno, T.; Tanaka, C. Antimuscarinic effects of antihistamines: Quantitative evaluation by receptor-binding assay. Jpn. J. Pharmacol. 1987, 43, 277-282.
61. Cardelus, I.; Anton, F.; Beleta, J.; Palacios, J. M. Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle. Eur. J. Pharmacol. 1999, 374, 249-254.
62. Hustveit, O.; Setekleiv, J. Fentanyl and pethidine are antagonists on muscarinic receptors in guinea-pig ileum. Acta Anaesthesiol. Scand. 1993, 37, 541-544.
63. Chen, Y. P.; Chen, S. R.; Pan, H. L. Systemic morphine inhibits dorsal horn projection neurons through spinal cholinergic system independent of descending pathways. J. Pharmacol. Exp. Ther. 2005, 314, 611-617.
64. Sofia, R. D.; Gordon, R.; Gels, M.; Diamantis, W. Comparative effects of felbamate and other compounds on N-methyl-D-aspartic acid-induced convulsions and lethality in mice. Pharmacol. Res. 1994, 29, 139-144.
65. 3H]noradrenaline overflow in rat cortical slices. Gen. Pharmacol. 1995, 26, 1603-1606.
66. Charlesworth, P.; Jacobson, I.; Richards, C. D. Pentobarbitone modulation of NMDA receptors in neurones isolated from the rat olfactory brain. Br. J. Pharmacol. 1995, 116, 3005-3013.
67. Harty, T. P.; Rogawski, M. A. Felbamate block of recombinant N-methyl-D-aspartate receptors: Selectivity for the NR2B subunit. Epilepsy Res. 2000, 39, 47-55.
68. Schwendt, M.; Duncko, R.; Makatsori, A.; Moncek, F.; Johansson, B. B.; Jezova, D. Involvement of glutamate neurotransmission in the development of excessive wheel running in Lewis rats. Neurochem. Res. 2003, 28, 653-657.
69. Tanaka, K.; Tomisato, W.; Hoshino, T.; Ishihara, T.; Namba, T.; Aburaya, M.; Katsu, T.; Suzuki, K.; Tsutsumi, S.; Mizushima, T. Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis. J. Biol. Chem. 2005, 280, 31059-31067.
70. Beltinger, C.; Fulda, S.; Kammertoens, T.; Uckert, W.; Debatin, K. M. Mitochondrial amplification of death signals determines thymidine kinase/ganciclovir-triggered activation of apoptosis. Cancer Res. 2000, 60, 3212-3217.
71. Shiff, S. J.; Koutsos, M. I.; Qiao, L.; Rigas, B. Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: Effects on cell cycle and apoptosis. Exp. Cell. Res. 1996, 222, 179-188.
72. Elder, D. J.; Halton, D. E.; Hague, A.; Paraskeva, C. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: Independence from COX-2 protein expression. Clin. Cancer Res. 1997, 3, 1679-1683.
73. Smith, M. L.; Hawcroft, G.; Hull, M. A. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: Evidence of different mechanisms of action. Eur. J. Cancer 2000, 36, 664-674.
74. Reinacher-Schick, A.; Schoeneck, A.; Graeven, U.; Schwarte-Waldhoff, I.; Schmiegel, W. Mesalazine causes a mitotic arrest and induces caspase-dependent apoptosis in colon carcinoma cells. Carcinogenesis 2003, 24, 443-451.
75. Bold, R. J.; Chandra, J.; McConkey, D. J. Gemcitabine-induced programmed cell death (apoptosis) of human pancreatic carcinoma is determined by Bcl-2 content. Ann. Surg. Oncol. 1999, 6, 279-285.
76. Schniewind, B.; Christgen, M.; Kurdow, R.; Haye, S.; Kremer, B.; Kalthoff, H.; Ungefroren, H. Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis. Int. J. Cancer 2004, 109, 182-188.
77. Mohammad, R. M.; Wang, S.; Banerjee, S.; Wu, X.; Chen, J.; Sarkar, F. H. Nonpeptidic small-molecule inhibitor of Bcl-2 and Bel-XL, (-)-Gossypol, enhances biological effect of genistein against BxPC-3 human pancreatic cancer cell line. Pancreas 2005, 31, 317-324.
78. Tolomeo, M.; Mancuso, S.; Todaro, M.; Stassi, G.; Catalane, M.; Arista, S.; Cannizzo, G.; Barbusca, E.; Abbadessa, V. Mitochondrial disruption and apoptosis in lymphocytes of an HIV infected patient affected by lactic acidosis after treatment with highly active antiretroviral therapy. J. Clin. Pathol. 2003, 56, 147-151.
79. Caron, M.; Auclair, M.; Lagathu, C.; Lombes, A.; Walker, U. A.; Kornprobst, M.; Capeau, J. The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. Aids 2004, 18, 2127-2136.
80. Oltersdorf, T.; Elmore, S. W.; Shoemaker, A. R.; Armstrong, R. C.; Augeri, D. J.; Belli, B. A.; Bruncko, M.; Deckwerth, T. L.; Dinges, J.; Hajduk, P. J.; Joseph, M. K.; Kitada, S.; Korsmeyer, S. J.; Kunzer, A. R.; Letai, A.; Li, C.; Mitten, M. J.; Nettesheim, D. G.; Ng, S.; Nimmer, P. M.; O'Connor, J. M.; Oleksijew, A.; Petras, A. M.; Reed, J. C.; Shen, W.; Tahir, S. K.; Thompson, C. B.; Tomaselli, K. J.; Wang, B.; Wendt, M. D.; Zhang, H.; Fesik, S. W.; Rosenberg, S. H. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005, 435, 677-681.
81. Mizuno, N.; Niwa, T.; Yotsumoto, Y.; Sugiyama, Y. Impact of drug transporter studies on drug discovery and development. Pharmacol. Rev. 2003, 55, 425-461.
82. Liang, R.; Fei, Y. J.; Prasad, P. D.; Ramamoorthy, S.; Han, H.; Yang-Feng, T. L.; Hediger, M. A.; Ganapathy, V.; Leibach, F. H. Human intestinal H+/peptide cotransporter. Cloning, functional expression, and chromosomal localization. J. Biol. Chem. 1995, 270, 6456-6463.
83. Schafer-Korting, M.; Kirch, W.; Axthelm, T.; Kohler, H.; Mutschler, E. Atenolol interaction with aspirin, allopurinol, and ampicillin. Clin. Pharmacol. Ther. 1983, 33, 283-288.
84. Van Bambeke, F.; Michot, J. M.; Tulkens, P. M. Antibiotic efflux pumps in eukaryotic cells: Occurrence and impact on antibiotic cellular pharmacokinetics, pharmacodynamics and toxicodynamics. J. Antimicrob. Chemother. 2003, 51, 1067-1077.
85. Ott, R. J.; Giacomini, K. M. Stereoselective interactions of organic cations with the organic cation transporter in OK cells. Pharm. Res. 1993, 10, 1169-1173.
86. Dudley, A. J.; Bleasby, K.; Brown, C. D. The organic cation transporter OCT2 mediates the uptake of beta-adrenoceptor antagonists across the apical membrane of renal LLC-PK(1) cell monolayers. Br. J. Pharmacol. 2000, 131, 71-79.
87. Kliewer, S. A.; Moore, J. T.; Wade, L.; Staudinger, J. L.; Watson, M. A.; Jones, S. A.; McKee, D. D.; Oliver, B. B.; Willson, T. M.; Zetterstrom, R. H.; Perlmann, T.; Lehmann, J. M. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998, 92, 73-82.
88. Matheny, C. J.; Lamb, M. W.; Brouwer, K. R.; Pollack, G. M. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001, 21, 778-796.
89. Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 12, 413-420.
90. Bailey, D. G.; Dresser, G. K. Interactions between grapefruit juice and cardiovascular drugs. Am. J. Cardiovasc. Drugs 2004, 4, 281-297.
91. Glue, P.; Banfield, C. R.; Perhach, J. L.; Mather, G. G.; Racha, J. K.; Levy, R. H. Pharmacokinetic interactions with felbamate. In vitro-in vivo correlation. Clin. Pharmacokinet. 1997, 33, 214-224.
92. Petrel, C.; Kessler, A.; Dauban, P.; Dodd, R. H.; Rognan, D.; Ruat, M. Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. J. Biol. Chem. 2004, 279, 18990-18997.
93. Petrel, C.; Kessler, A.; Maslah, F.; Dauban, P.; Dodd, R. H.; Rognan, D.; Ruat, M. Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca-(2+)-sensing receptor. J. Biol. Chem. 2003, 278, 49487-49494.
94. Gombar, V. K.; Polli, J. W.; Humphreys, J. E.; Wring, S. A.; Serabjit-Singh, C. S. Predicting P-glycoprotein substrates by a quantitative structure-activity relationship model. J. Pharm. Sci. 2004, 93, 957-968.