Plasma protein binding affinity and its relationship to molecular structure: An in-silico analysis

Journal of Medicinal Chemistry

Volumn 50, Issue 1, 2007, Pages 101-112

  Gleeson, M Paul ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; CHEMICAL STRUCTURE; MULTIVARIATE ANALYSIS; PARTIAL LEAST SQUARES REGRESSION; PLASMA PROTEIN BINDING; PREDICTION; UNIVARIATE ANALYSIS;

ANALYSIS OF VARIANCE; ANIMALS; BLOOD PROTEINS; DATABASES, FACTUAL; HUMANS; MODELS, BIOLOGICAL; MOLECULAR STRUCTURE; PHARMACEUTICAL PREPARATIONS; PROTEIN BINDING; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RATS;

EID: 33846230530     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060981b     Document Type: Article

References (32)

1. Grandison, M. K.; Boudinot, F. D. Age-related changes in protein binding of drugs. Implications for therapy. Clin. Pharmacokinet. 2000, 38, 271-290.
2. Benet, L. Z.; Hoener, B. A. Changes in plasma protein binding have little clinical relevance. Clin. Pharmacol. Ther. 2002, 71, 115-121.
3. Klippert, P.; Borm, P.; Noordhoek, J. Prediction of intestinal first-pass effect of phenacetin in the rat from enzyme kinetic data - correlation with in vivo data using mucosal blood flow. Biochem. Pharmacol Pharmacol. 1982, 31, 2545-2548
4. Oie, S.; Tozer, T. N. Effect of altered plasma protein binding on apparent volume of distribution. J. Pharm. Sci. 1979, 68, 1203-1205.
5. Kratochwil, N. A.; Huber, W.; Muller, F.; Kansy, M.; Gerber, P. R. Plasma protein binding of drugs. A new approach. Biochem. Pharmacol. 2002, 64, 1355-1374.
6. Colmenarejo, G.; Alvarez-Pedraglio, A.; Lavandera, J. L. Chemin-formatic models to predict binding affinities to human serum albumin. J. Med. Chem. 2001, 44, 4370-4378.
7. a and AlogP98 values. Mol. Diversity 2003, 7, 69-87.
8. Yamakazi, K.; Kanaoka, M. Computational Prediction of plasma protein binding Percent of diverse pharmaceutical compounds. J. Pharm. Sci. 2004, 93, 1480-1494.
9. Saiakhov, R. D.; Stefan, L. R.; Klopman, G. Multiple computer-automated structure evaluation model of plasma protein binding affinity of diverse drugs. Perspect. Drug Discovery 2000, 19, 133-155.
10. Austin, R. P.; Barton, P.; Mohmed, S.; Riley, R. J. The binding of drugs to hepatocytes and its relationship to physicochemical properties. Drug Metab. Disp. 2005, 33, 419-425.
11. Singh, S. S.; Mehta, J. Measurement of drug-protein binding by immobilized human serum albumin-HPLC and comparison with ultrafiltration. J. Chromat. B 2006, 834, 108-116.
12. Valko, K.; Nunhuck, S.; Bevan, C.; Abraham, M. H.; Reynolds, D. P. Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol/water and immobilized artificial membrane lipophilicity. J. Pharm. Sci. 2003, 92, 2236-2248.
13. ss quantitative structure-activity relationship models. J. Med. Chem. 2006, 49, 1953-1963.
14. Stouch, T. R.; Kenyon, J. R.; Johnson, S. R.; Chen, X. Q.; Doweyko, A.; Li, Y. J. In silico ADME/Tox: why models fail. Comput.-Aided Mol. Des. 2003, 17, 83-92.
15. Zlotos, G.; Bucker, A.; Kinzig-Schippers, M.; Sorgel, F.; Holzgrabe, U. Plasma protein binding of gyrase inhibitors. J. Pharm. Sci. 1998, 87, 215-220.
16. Advanced Chemistry Development, Inc., 110 Yonge Street, 14th Floor, Toronto, Ontario, M5C 1T4, Canada. http://www.acdlabs.com.
17. Ka base)+1)]; %zwitterion = smaller of [%deprotonated/2 or %protonated/2], %basic = [%protonated - %zwitterion], %acidic = [%deprotonated - %zwitterion], %neutral = 100 - %acid - %basic - %zwitterion.
18. Ertl, P.; Rohde, B.; Selzer, P. J. Fast calculation of molecular polar surface area as a sum of fragment based contributions and its application to the prediction of drug transport properties. J. Med. Chem. 2000, 43, 3714-3717.
19. Abraham, M. H.; Chadha, H. S.; Mitchell, R. C. Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain. J. Pharm. Sci. 1994, 83, 1257-1268.
20. Andrews, P. R.; Craik, D. J.; Martin, J. L. Functional group contributions to drug-receptor interactions, J. Med. Chem. 1984, 27, 1648-1657.
21. Daylight Chemical Information Systems, Inc., 120 Vantis, Suite 550, Aliso Viejo, CA 92656. http://www.daylight.com.
22. The ionization state of a molecule was defined based on the presence or absence of acidic or basic functional groups which are predominantly in the ionized form at pH 7.4. Neutral molecules had none of the in-house defined functional groups, while zwitterions had at least one acidic and one basic group present.
23. Statistica 7.1, Statsoft Inc, 2300 East Tulsa, OK 74104, U.S.A, http:// www.statsoft.com.
24. Höskuldsson, A. Prediction Methods in Science and Technology, Thor Publishing: Copenhagen, Denmark, 1996.
25. Wold, S.; Albano, C.; Dunn, W. J.; Edlund, U.; Esbensen, K.; Geladi, P.; Hellberg, S.; Johansson, E.; Lindberg, W.; Sjöström, M. Multivariate Data Analysis in Chemistry, In Chemometrics: Mathematics and Statistics in Chemistry; B. R. Kowalski, Ed.; D. Reidel Publishing Company: Dordrecht, Holland, 1984.
26. Wold, S.; Eriksson, L.; Sjöström, M. PLS in Chemistry, Encyclopedia of Computational Chemistry, Wiley: New York, 2000.
27. GOLPE: Multivariate Infometric Analysis Srl., Viale dei Castagni 16, Perugia, Italy.
28. SIMCA-P 10, Umetrics, Tvistevägen 48, Box 7960, SE-907 19 Umeå, Sweden.
29. JMP 6.0, JMP Europe, SAS Institute, Henley Road, Medmenham, Marlow, SL7 2EB UK, http://www.jmp.com.
30. Statistica System Reference, Statsoft Inc, 2300 East Tulsa, OK74104, USA, http://www.statsoft.com.
31. 2 to give eq 5.
32. The one-way ANOVA results and the two-way ANOVA results associated with Figure 1 are statistically significant above the 95% confidence level, indicating both ionization state and logP have an independent impact on the extent of protein binding. Two-tailed T-tests between the different ionization states indicate the logK values of neutrals and zwitterions are equivalent but those for acids and bases are significantly different. The same tests indicate the affect of increasing logP, as given by the <3, 3-5 & >5 bins, are also statistically significantly different.