Evaluation of computational docking to identify pregnane X receptor agonists in the toxcast database

Environmental Health Perspectives

Volumn 118, Issue 10, 2010, Pages 1412-1417

  Kortagere, Sandhya ^a   Krasowski, Matthew D ^b,g   Reschly, Erica J ^b   Venkatesh, Madhukumar ^c   Mani, Sridhar ^c   Ekins, Sean ^d,e,f  

^a DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^c ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^d Collaborations in Chemistry ^*  (United States)

^e UNIVERSITY OF MARYLAND   (United States)

^f RUTGERS ROBERT WOOD JOHNSON MEDICAL SCHOOL   (United States)

^g UNIVERSITY OF IOWA HOSPITALS AND CLINICS   (United States)

Author keywords

Bayesian model; Docking; Goldscore; Hybrid scoring; Pxr; Toxcast

Indexed keywords

2,4 DICHLOROPHENOXYACETIC ACID; ALACHLOR; BENSULIDE; BUTAFENACIL; CIPERMETHRIN; CYFLUTHRIN; DIURON; ENILCONAZOLE; FENARIMOL; FENBUCONAZOLE; FENPYROXIMATE; FENVALERATE; FORAMSULFURON; LIGAND; LUCIFERASE; MANCOZEB; METHYL HYDROGEN PHTHALATE; METHYLBENSULFURON; METHYLMESOSULFURON; METHYLTRIFLUSULFURON; OXADIAZON; OXASULFURON; PERMETHRIN; PHTHALIC ACID BIS(2 ETHYLHEXYL) ESTER; PREGNANE X RECEPTOR; PREGNANE X RECEPTOR AGONIST; PROCHLORAZ; PROPICONAZOLE; TOXIC SUBSTANCE; UNCLASSIFIED DRUG;

ARTICLE; BAYES THEOREM; CELL LINE; CELL STRAIN HEPG2; CELL VIABILITY; CLASSIFICATION; CONTROLLED STUDY; DATA BASE; DPX 2 CELL LINE; HUMAN; HUMAN CELL; IC 50; LIVER CELL; MOLECULAR DOCKING; PRIORITY JOURNAL; REPORTER GENE; SENSITIVITY ANALYSIS;

BAYES THEOREM; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DATABASES, FACTUAL; GENES, REPORTER; HUMANS; RECEPTORS, STEROID;

EID: 77957903965     PISSN: 00916765     EISSN: 15529924     Source Type: Journal    
DOI: 10.1289/ehp.1001930     Document Type: Article

References (53)

1. Bachmann K, Patel H, Batayneh Z, Slama J, White D, Posey J, et al. 2004. PXR and the regulation of apoA1 and HDL-cholesterol in rodents. Pharmacol Res 50(3):237-246.
2. Biswas A, Mani S, Redinbo MR, Krasowski MD, Li H, Ekins S. 2009. Elucidating the 'Jekyll and Hyde' nature of PXR: the case for discovering antagonists. Pharm Res 26:1807-1815.
3. Chekmarev D, Kholodovych V, Kortagere S, Welsh WJ, Ekins S. 2009. Predicting Inhibitors of acetylcholinesterase by regression and classification machine learning approaches with combinations of molecular descriptors. Pharm Res 26:2216-2224.
4. Chekmarev DS, Kholodovych V, Balakin KV, Ivanenkov Y, Ekins S, Welsh WJ. 2008. Shape signatures: new descriptors for predicting cardiotoxicity in silico. Chem Res Toxicol 21:1304-1314.
5. Chrencik JE, Orans J, Moore LB, Xue Y, Peng L, Collins JL, et al. 2005. Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol Endocrinol 19(5):1125-1134.
6. Dimitrov S, Dimitrova G, Pavlov T, Dimitrova N, Patlewicz G, Niemela J, et al. 2005. A stepwise approach for defining the applicability domain of SAR and QSAR models. J Chem Inf Model 45(4):839-849.
7. Dix DJ, Houck KA, Martin MT, Richard AM, Setzer RW, Kavlock RJ. 2007. The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol Sci 95(1):5-12.
8. Ekins S, Andreyev S, Ryabov A, Kirillov E, Rakhmatulin EA, Sorokina S, et al. 2006. A combined approach to drug metabolism and toxicity assessment. Drug Metab Dispos 34:495-503.
9. Ekins S, Chang C, Mani S, Krasowski MD, Reschly EJ, Iyer M, et al. 2007. Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol Pharmacol 72:592-603.
10. Ekins S, Erickson JA. 2002. A pharmacophore for human pregnane-X-receptor ligands. Drug Metab Dispos 30:96-99.
11. Ekins S, Kholodovych V, Ai N, Sinz M, Gal J, Gera L, et al. 2008a. Computational discovery of novel low micromolar human pregnane X receptor antagonists. Mol Pharmacol 74(3):662-672.
12. Ekins S, Kortagere S, Iyer M, Reschly EJ, Lill MA, Redinbo M, et al. 2009. Challenges predicting ligand-receptor interactions of promiscuous proteins: the nuclear receptor PXR. PLoS Comput Biol 5:e1000594; doi:10.1371/journal.pcbi.1000594 [Online 11 December 2009].
13. Ekins S, Reschly EJ, Hagey LR, Krasowski MD. 2008b. Evolution of pharmacologic specificity in the pregnane X receptor. BMC Evol Biol 8:103; doi:10.1186/1471-2148-8-103 [Online 2 April 2008].
14. Houck KA, Dix DJ, Judson RS, Kavlock RJ, Yang J, Berg EL. 2009. Profiling bioactivity of the ToxCast chemical library using BioMAP primary human cell systems. J Biomol Screen 14(9):1054-1066.
15. Hurst CH, Waxman DJ. 2004. Environmental phthalate monoesters activate pregnane X receptor-mediated transcription. Toxicol Appl Pharmacol 199(3):266-274.
16. Jacobs MN. 2004. In silico tools to aid risk assessment of endocrine disrupting chemicals. Toxicology 205(1-2):43-53.
17. Jones G, Willett P, Glen RC, Leach AR, Taylor R. 1997. Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267(3):727-748.
18. Judson R, Richard A, Dix DJ, Houck K, Martin M, Kavlock R, et al. 2009. The toxicity data landscape for environmental chemicals. Environ Health Perspect 117:685-695.
19. Judson RS, Houck KA, Kavlock RJ, Knudsen TB, Martin MT, Mortensen HM, et al. 2010. In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project. Environ Health Perspect 118:485-492.
20. Khandelwal A, Krasowski MD, Reschly EJ, Sinz MW, Swaan PW, Ekins S. 2008. Machine learning methods and docking for predicting human pregnane X receptor activation. Chem Res Toxicol 21:1457-1467.
21. Knight AW, Little S, Houck K, Dix D, Judson R, Richard A, et al. 2009. Evaluation of high-throughput genotoxicity assays used in profiling the US EPA ToxCast chemicals. Regul Toxicol Pharmacol 55(2):188-199.
22. Kortagere S, Chekmarev DS, Welsh WJ, Ekins S. 2008. New predictive models for blood brain barrier permeability of drug-like molecules. Pharm Res 25:1836-1845.
23. Kortagere S, Chekmarev D, Welsh WJ, Ekins S. 2009. Hybrid scoring and classification approaches to predict human pregnane X receptor activators. Pharm Res 26:1001-1011.
24. Krasowski MD, Yasuda K, Hagey LR, Schuetz EG. 2005a. Evolution of the pregnane x receptor: adaptation to cross-species differences in biliary bile salts. Mol Endocrinol 19(7):1720-1739.
25. Krasowski MD, Yasuda K, Hagey LR, Schuetz EG. 2005b. Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors). Nucl Recept 3(1):2; doi:10.1186/1478-1336-3-2 [Online 30 September 2005].
26. Lemaire G, Mnif W, Pascussi JM, Pillon A, Rabenoelina F, Fenet H, et al. 2006. Identification of new human pregnane X receptor ligands among pesticides using a stable reporter cell system. Toxicol Sci 91(2):501-509.
27. Mani S, Ghalib M, Chaudhary I, Goel S. 2009. Alterations of chemotherapeutic pharmacokinetic profiles by drug-drug interactions. Expert Opin Drug Metab Toxicol 5(2):109-130.
28. Mnif W, Pascussi JM, Pillion A, Escande A, Bartegi A, Nicolas JC, et al. 2007. Estrogens and antiestrogens activate PXR. Toxicol Lett 170:19-29.
29. Moore LB, Maglich JM, McKee DD, Wisely B, Willson TM, Kliewer SA, et al. 2002. Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors. Mol Endocrinol 16(5):977-986.
30. Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, et al. 2000. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem 275(20):15122-15127.
31. Ngan CH, Beglov D, Rudnitskaya AN, Kozakov D, Waxman DJ, Vajda S. 2009. The structural basis of pregnane X receptor binding promiscuity. Biochemistry 48(48):11572-11581.
32. Reschly EJ, Ai N, Ekins S, Welsh WJ, Hagey LR, Hofmann AF, et al. 2008a. Evolution of the bile salt nuclear receptor FXR in vertebrates. J Lipid Res 49(7):1577-1587.
33. Reschly EJ, Ai N, Welsh WJ, Ekins S, Hagey LR, Krasowski MD. 2008b. Ligand specificity and evolution of liver X receptors. J Steroid Biochem Mol Biol 110(1-2):83-94.
34. Reschly EJ, Bainy AC, Mattos JJ, Hagey LR, Bahary N, Mada SR, et al. 2007. Functional evolution of the vitamin D and pregnane X receptors. BMC Evol Biol 7(1):222; doi:10.1186/1471-2148-7-222 [Online 12 November 2007].
35. Reschly EJ, Krasowski MD. 2006. Evolution and function of the NR1I nuclear hormone receptor subfamily (VDR, PXR, and CAR) with respect to metabolism of xenobiotics and endogenous compounds. Curr Drug Metab 7(4):349-365.
36. Schuster D, Langer T. 2005. The identification of ligand features essential for PXR activation by pharmacophore modeling. J Chem Inf Model 45(2):431-439.
37. Sheridan RP, Feuston BP, Maiorov VN, Kearsley SK. 2004. Similarity to molecules in the training set is a good discriminator for prediction accuracy in QSAR. J Chem Inf Comput Sci 44(6):1912-1928.
38. Teotico DG, Bischof JJ, Peng L, Kliewer SA, Redinbo MR. 2008. Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Mol Pharmacol 74(6):1512-1520.
39. Tetko IV, Bruneau P, Mewes HW, Rohrer DC, Poda GI. 2006. Can we estimate the accuracy of ADME-Tox predictions? Drug Discov Today 11(15-16):700-707.
40. Tetko IV, Sushko I, Pandey AK, Zhu H, Tropsha A, Papa E, et al. 2008. Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: focusing on applicability domain and overfitting by variable selection. J Chem Inf Model 48(9):1733-1746.
41. Tirona RG, Leake BF, Podust LM, Kim RB. 2004. Identification of amino acids in rat pregnane X receptor that determine species-specific activation. Mol Pharmacol 65(1):36-44.
42. Tirona RG, Lee W, Leake BF, Lan L-B, Brimer Cline C, Lamba V, et al. 2003. The orphan nuclear receptor HNF4alpha determines PXR- and CAR mediated xenobiotic induction of CYP3A4. Nat Med 9:220-224.
43. Ung CY, Li H, Yap CW, Chen YZ. 2007. In silico prediction of pregnane X receptor activators by machine learning approaches. Mol Pharmacol 71(1):158-168.
44. U.S. EPA (U.S. Environmental Protection Agency). 2009. SDF Download Page. TOXCST: Research Chemical Inventory for EPA's ToxCast™ Program. Structure-Index File. Available: http://www.epa.gov/ncct/dsstox/sdf_toxcst.html#DownloadTable [accessed 7 September 2010].
45. U.S. EPA (U.S. Environmental Protection Agency). 2010. ToxCastTM: Predicting Hazard, Characterizing Toxicity Pathways, and Prioritizing the Toxicity Testing of Environmental Chemicals. Available: http://www.epa.gov/ncct/toxcast/ [accessed 1 September 2010].
46. Wada T, Gao J, Xie W. 2009. PXR and CAR in energy metabolism. Trends Endocrinol Metab 20(6):273-279.
47. Watkins RE, Davis-Searles PR, Lambert MH, Redinbo MR. 2003a. Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J Mol Biol 331:815-828.
48. Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, et al. 2003b. 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry 42:1430-1438.
49. Willett P. 2003. Similarity-based approaches to virtual screening. Biochem Soc Trans 31:603-606.
50. Xue Y, Chao E, Zuercher WJ, Willson TM, Collins JL, Redinbo MR. 2007a. Crystal structure of the PXR-T1317 complex provides a scaffold to examine the potential for receptor antagonism. Bioorg Med Chem 15(5):2156-2166.
51. Xue Y, Moore LB, Orans J, Peng L, Bencharit S, Kliewer SA, et al. 2007b. Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition. Mol Endocrinol 21(5):1028-1038.
52. Yasuda K, Ranade A, Venkataramanan R, Strom S, Chupka J, Ekins S, et al. 2008. A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos 36(8):1689-1697.
53. Zhai Y, Pai HV, Zhou J, Amico JA, Vollmer RR, Xie W. 2007. Activation of pregnane X receptor disrupts glucocorticoid and mineralocorticoid homeostasis. Mol Endocrinol 21:138-147.