Activity-limiting role of molecular size: Size-dependency of maximum activity for P450 inhibition as revealed by qHTS data

Drug Metabolism and Disposition

Volumn 42, Issue 11, 2014, Pages 1785-1790

  Buchwald, Peter ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450; CYTOCHROME P450 1A2; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; ENVIRONMENTAL CHEMICAL; CYTOCHROME P450 INHIBITOR;

ARTICLE; BIOASSAY; DATA BASE; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; IC50; MOLECULAR SIZE; NONLINEAR SYSTEM; QUANTITATIVE ANALYSIS; STATISTICAL MODEL; STRUCTURE ANALYSIS;

CYTOCHROME P-450 ENZYME INHIBITORS; HIGH-THROUGHPUT SCREENING ASSAYS;

EID: 84907441857     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.114.059717     Document Type: Article

References (36)

1. Bodor N and Buchwald P (2012) Retrometabolic Drug Design and Targeting, Wiley, Hoboken, NJ.
2. Buchwald P (2005) General linearized biexponential model for QSAR data showing bilinear-type distribution. J Pharm Sci 94:2355-2379.
3. Buchwald P (2007) A general bilinear model to describe growth or decline time profiles. Math Biosci 205:108-136.
4. Buchwald P (2008) Glucocorticoid receptor binding: a biphasic dependence on molecular size as revealed by the bilinear LinBiExp model. Steroids 73:193-208.
5. Buchwald P and Bodor N (1998) Octanol-water partition: searching for predictive models. Curr Med Chem 5:353-380.
6. Buchwald P and Bodor N (2000) Simple model for nonassociative organic liquids and water. J Am Chem Soc 122:10671-10679.
7. Buchwald P and Bodor N (2006) Soft quaternary anticholinergics: comprehensive QSAR with a linearized biexponential (LinBiExp) model. J Med Chem 49:883-891.
8. Buchwald P and Yamashita F (2014) Bilinear model for the size-dependency of the CYP3A4 inhibitory activity of structurally diverse compounds. Mol Inform 33:8-14.
9. Cheng F, Yu Y, Shen J, Yang L, LiW, Liu G, Lee PW, and Tang Y (2011) Classification of cytochrome P450 inhibitors and noninhibitors using combined classifiers. J Chem Inf Model 51:996-1011.
10. Choi I, Kim SY, Kim H, Kang NS, Bae MA, Yoo SE, Jung J, and No KT (2009) Classification models for CYP450 3A4 inhibitors and non-inhibitors. Eur J Med Chem 44:2354-2360.
11. Ekins S, Bravi G, Binkley S, Gillespie JS, Ring BJ, Wikel JH, and Wrighton SA (1999) Threeand four-dimensional quantitative structure activity relationship analyses of cytochrome P-450 3A4 inhibitors. J Pharmacol Exp Ther 290:429-438.
12. Gleeson MP (2008) Generation of a set of simple, interpretable ADMET rules of thumb. J Med Chem 51:817-834.
13. Gleeson MP, Davis AM, Chohan KK, Paine SW, Boyer S, Gavaghan CL, Arnby CH, Kankkonen C, and Albertson N (2007) Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models. J Comput Aided Mol Des 21:559-573.
14. Hajduk PJ (2006) Fragment-based drug design: how big is too big? J Med Chem 49:6972-6976.
15. Hajduk PJ and Greer J (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 6:211-219.
16. Hansch C, Mekapati SB, Kurup A, and Verma RP (2004) QSAR of cytochrome P450. Drug Metab Rev 36:105-156.
17. Hopkins AL, Groom CR, and Alex A (2004) Ligand efficiency: a useful metric for lead selection. Drug Discov Today 9:430-431.
18. Hopkins AL, Keserü GM, Leeson PD, Rees DC, and Reynolds CH (2014) The role of ligand efficiency metrics in drug discovery. Nat Rev Drug Discov 13:105-121.
19. Horváth A, Rácz-Mónus A, Buchwald P, and Sveiczer Á (2013) Cell length growth in fission yeast: an analysis of its bilinear character and the nature of its rate change transition. FEMS Yeast Res 13:635-649.
20. Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, and Austin CP (2006) Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci USA 103:11473-11478.
21. Jensen BF, Vind C, Padkjaer SB, Brockhoff PB, and Refsgaard HH (2007) In silico prediction of cytochrome P450 2D6 and 3A4 inhibition using Gaussian kernel weighted k-nearest neighbor and extended connectivity fingerprints, including structural fragment analysis of inhibitors versus noninhibitors. J Med Chem 50:501-511.
22. Lewis DF, Modi S, and Dickins M (2001) Quantitative structure-activity relationships (QSARs) within substrates of human cytochromes P450 involved in drug metabolism. Drug Metabol Drug Interact 18:221-242.
23. Lin JH and Lu AY (1997) Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol Rev 49:403-449.
24. Mao B, Gozalbes R, Barbosa F, Migeon J, Merrick S, Kamm K, Wong E, Costales C, Shi W, and Wu C, et al. (2006) QSAR modeling of in vitro inhibition of cytochrome P450 3A4. J Chem Inf Model 46:2125-2134.
25. Reynolds CH, Bembenek SD, and Tounge BA (2007) The role of molecular size in ligand efficiency. Bioorg Med Chem Lett 17:4258-4261.
26. Riley RJ, Parker AJ, Trigg S, and Manners CN (2001) Development of a generalized, quantitative physicochemical model of CYP3A4 inhibition for use in early drug discovery. Pharm Res 18: 652-655.
27. Stoll F, Göller AH, and Hillisch A (2011) Utility of protein structures in overcoming ADMETrelated issues of drug-like compounds. Drug Discov Today 16:530-538.
28. Sun H, Veith H, Xia M, Austin CP, Tice RR, and Huang R (2012) Prediction of cytochrome P450 profiles of environmental chemicals with QSAR models built from drug-like molecules. Mol Inform 31:783-792.
29. Tice RR, Austin CP, Kavlock RJ, and Bucher JR (2013) Improving the human hazard characterization of chemicals: a Tox21 update. Environ Health Perspect 121:756-765.
30. van de Waterbeemd H and Gifford E (2003) ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov 2:192-204.
31. Veith H, Southall N, Huang R, James T, Fayne D, Artemenko N, Shen M, Inglese J, Austin CP, and Lloyd DG, et al. (2009) Comprehensive characterization of cytochrome P450 isozyme selectivity across chemical libraries. Nat Biotechnol 27:1050-1055.
32. Wanchana S, Yamashita F, and Hashida M (2003) QSAR analysis of the inhibition of recombinant CYP 3A4 activity by structurally diverse compounds using a genetic algorithmcombined partial least squares method. Pharm Res 20:1401-1408.
33. Wienkers LC and Heath TG (2005) Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 4:825-833.
34. Yamashita F, Hara H, Ito T, and Hashida M (2008) Novel hierarchical classification and visualization method for multiobjective optimization of drug properties: application to structureactivity relationship analysis of cytochrome P450 metabolism. J Chem Inf Model 48:364-369.
35. Yamashita F, Feng C, Yoshida S, Itoh T, and Hashida M (2011) Automated information extraction and structure-activity relationship analysis of cytochrome P450 substrates. J Chem Inf Model 51:378-385.
36. Yang Y, Engkvist O, Llinàs A, and Chen H (2012) Beyond size, ionization state, and lipophilicity: influence of molecular topology on absorption, distribution, metabolism, excretion, and toxicity for druglike compounds. J Med Chem 55:3667-3677.