Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein.
- 1 May 2002
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 61 (5), 964-973
- https://doi.org/10.1124/mol.61.5.964
Abstract
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/VLB100cells 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.Keywords
This publication has 23 references indexed in Scilit:
- Identification of the Cyclosporin-Binding Site in P-GlycoproteinBiochemistry, 1998
- Molecular Modeling of Phenothiazines and Related Drugs As Multidrug Resistance Modifiers: A Comparative Molecular Field Analysis StudyJournal of Medicinal Chemistry, 1998
- The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.JCI Insight, 1998
- Positively Cooperative Sites for Drug Transport by P‐Glycoprotein with Distinct Drug SpecificitiesJBIC Journal of Biological Inorganic Chemistry, 1997
- Ranking of P-glycoprotein substrates and inhibitors by a calcein-AM fluorometry screening assayAnti-Cancer Drugs, 1996
- Co-operative, competitive and non-competitive interactions between modulators of P-glycoproteinBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1996
- Competition of Hydrophobic Peptides, Cytotoxic Drugs, and Chemosensitizers on a Common P-glycoprotein Pharmacophore as Revealed by Its ATPase ActivityPublished by Elsevier BV ,1996
- Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A.JCI Insight, 1995
- Structural characteristics of compounds that modulate P-glycoprotein-associated multidrug resistanceAdvances in Enzyme Regulation, 1990
- SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rulesJournal of Chemical Information and Computer Sciences, 1988