MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ekins, S.
Right arrow Articles by Wrighton, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ekins, S.
Right arrow Articles by Wrighton, S. A.

Vol. 61, Issue 5, 964-973, May 2002

Three-Dimensional Quantitative Structure-Activity Relationships of Inhibitors of P-Glycoprotein

Sean Ekins, Richard B. Kim, Brenda F. Leake, Anne H. Dantzig, Erin G. Schuetz, Lu-Bin Lan, Kazuto Yasuda, Robert L. Shepard, Mark A. Winter, John D. Schuetz, James H. Wikel, and Steven A. Wrighton

Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana (S.E., A.H.D., R.L.S., M.A.W., J.H.W., S.A.W.); Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee (R.B.K., B.F.L.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (E.G.S., L.-B.L., K.Y., J.D.S.)

P-glycoprotein (P-gp) is an efflux transporter involved in limiting the oral bioavailability and tissue penetration of a variety of structurally divergent molecules. A better understanding of the structural requirements of modulators of P-gp function will aid in the design of therapeutic agents. Toward this goal, three-dimensional quantitative structure-activity relationship (3D-QSAR) models were generated using in vitro data associated with inhibition of P-gp function. Several approaches were undertaken with multiple iterations, yielding Catalyst 3D-QSAR models being able to qualitatively rank-order and predict IC50 values for P-gp inhibitors excluded from the model in question. The success of these validations suggests that a P-gp pharmacophore for 27 inhibitors of digoxin transport in Caco-2 cells consisted of four hydrophobes and one hydrogen bond acceptor. A second pharmacophore generated with 21 inhibitors of vinblastine binding to plasma membrane vesicles derived from CEM/VLB100 cells contained three ring aromatic features and one hydrophobic feature. A third pharmacophore generated with 17 inhibitors of vinblastine accumulation in P-gp expressing LLC-PK1 cells contained four hydrophobes and one hydrogen bond acceptor. A final pharmacophore was generated for inhibition of calcein accumulation in P-gp expressing LLC-PK1 cells and found to contain two hydrophobes, a ring aromatic feature, and a hydrogen bond donor. The similarity of features for the pharmacophores of P-gp inhibitors of digoxin transport and vinblastine binding suggest some commonality in their binding sites. Utilization of such models may prove to be of value for prediction of molecules that may modulate one or more P-gp binding sites.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
C. Chang, P. M. Bahadduri, J. E. Polli, P. W. Swaan, and S. Ekins
Rapid Identification of P-glycoprotein Substrates and Inhibitors
Drug Metab. Dispos., December 1, 2006; 34(12): 1976 - 1984.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. A. Gabizon, D. Tzemach, A. T. Horowitz, H. Shmeeda, J. Yeh, and S. Zalipsky
Reduced toxicity and superior therapeutic activity of a mitomycin C lipid-based prodrug incorporated in pegylated liposomes.
Clin. Cancer Res., March 15, 2006; 12(6): 1913 - 1920.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
M. E. Taub, L. Podila, D. Ely, and I. Almeida
FUNCTIONAL ASSESSMENT OF MULTIPLE P-GLYCOPROTEIN (P-GP) PROBE SUBSTRATES: INFLUENCE OF CELL LINE AND MODULATOR CONCENTRATION ON P-GP ACTIVITY
Drug Metab. Dispos., November 1, 2005; 33(11): 1679 - 1687.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Abad-Merin, N. Cortes, I. Masip, E. Perez-Paya, J. A. Ferragut, A. Messeguer, and A. Ferrer-Montiel
Trimers of N-Alkylglycines Are Potent Modulators of the Multidrug Resistance Phenotype
J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 112 - 120.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
C. Chang, P. W. Swaan, L. Y. Ngo, P. Y. Lum, S. D. Patil, and J. D. Unadkat
Molecular Requirements of the Human Nucleoside Transporters hCNT1, hCNT2, and hENT1
Mol. Pharmacol., March 1, 2004; 65(3): 558 - 570.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama
Impact of Drug Transporter Studies on Drug Discovery and Development
Pharmacol. Rev., September 1, 2003; 55(3): 425 - 461.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. Weiss, S.-M. G. Dormann, M. Martin-Facklam, C. J. Kerpen, N. Ketabi-Kiyanvash, and W. E. Haefeli
Inhibition of P-Glycoprotein by Newer Antidepressants
J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 197 - 204.
[Abstract] [Full Text]

Home page
 Mol. Pharmacol.Home page
D. Bednarczyk, S. Ekins, J. H. Wikel, and S. H. Wright
Influence of Molecular Structure on Substrate Binding to the Human Organic Cation Transporter, hOCT1
Mol. Pharmacol., March 1, 2003; 63(3): 489 - 498.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. Garrigues, N. Loiseau, M. Delaforge, J. Ferte, M. Garrigos, F. Andre, and S. Orlowski
Characterization of Two Pharmacophores on the Multidrug Transporter P-Glycoprotein
Mol. Pharmacol., December 1, 2002; 62(6): 1288 - 1298.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
K. Yasuda, L.-b. Lan, D. Sanglard, K. Furuya, J. D. Schuetz, and E. G. Schuetz
Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein
J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 323 - 332.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. Ekins, R. B. Kim, B. F. Leake, A. H. Dantzig, E. G. Schuetz, L.-B. Lan, K. Yasuda, R. L. Shepard, M. a Winter, J. D. Schuetz, et al.
Application of Three-Dimensional Quantitative Structure-Activity Relationships of P-Glycoprotein Inhibitors and Substrates
Mol. Pharmacol., May 1, 2002; 61(5): 974 - 981.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics