Predicting P-glycoprotein substrates by a quantitative structure-activity relationship model.

A quantitative structure-activity relationship (QSAR) model has been developed to predict whether a given compound is a P-glycoprotein (Pgp) substrate or not. The training set consisted of 95 compounds classified as substrates or non-substrates based on the results from in vitro monolayer efflux assays. The two-group linear discriminant model uses 27 statistically significant, information-rich structure quantifiers to compute the probability of a given structure to be a Pgp substrate. Analysis of the descriptors revealed that the ability to partition into membranes, molecular bulk, and the counts and electrotopological values of certain isolated and bonded hydrides are important structural attributes of substrates. The model fits the data with sensitivity of 100% and specificity of 90.6% in the jackknifed cross-validation test. A prediction accuracy of 86.2% was obtained on a test set of 58 compounds. Examination of the eight "mispredicted" compounds revealed two distinct categories. Five mispredictions were explained by experimental limitations of the efflux assay; these compounds had high permeability and/or were inhibitors of calcein-AM transport. Three mispredictions were due to limitations of the chemical space covered by the current model. The Pgp QSAR model provides an in silico screen to aid in compound selection and in vitro efflux assay prioritization.

[1]  A. Seelig.  A general pattern for substrate recognition by P-glycoprotein. , 1998, European journal of biochemistry.

[2]  J. Polli,et al.  Midazolam Exhibits Characteristics of a Highly Permeable P-Glycoprotein Substrate , 2003, Pharmaceutical Research.

[3]  S. Ekins,et al.  Progress in predicting human ADME parameters in silico. , 2000, Journal of pharmacological and toxicological methods.

[4]  L. Kier.  Shape Indexes of Orders One and Three from Molecular Graphs , 1986 .

[5]  Y. Assaraf,et al.  The Role of Passive Transbilayer Drug Movement in Multidrug Resistance and Its Modulation* , 1996, The Journal of Biological Chemistry.

[6]  Lowell H. Hall,et al.  Modeling Antileukemic Activity of Carboquinones with Electrotopological State and Chi Indices , 1999, J. Chem. Inf. Comput. Sci..

[7]  C. Lipinski.  Drug-like properties and the causes of poor solubility and poor permeability. , 2000, Journal of pharmacological and toxicological methods.

[8]  L. Hall,et al.  Molecular Structure Description: The Electrotopological State , 1999 .

[9]  Lemont B. Kier,et al.  E-state fields: Applications to 3D QSAR , 1996, J. Comput. Aided Mol. Des..

[10]  Vijay K Gombar,et al.  Role of ADME characteristics in drug discovery and their in silico evaluation: in silico screening of chemicals for their metabolic stability. , 2003, Current topics in medicinal chemistry.

[11]  A. Seelig,et al.  Structure-activity relationship of P-glycoprotein substrates and modifiers. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[12]  James E. Polli,et al.  Influence of Passive Permeability on Apparent P-glycoprotein Kinetics , 2000, Pharmaceutical Research.

[13]  K. Brouwer,et al.  Secretory Transport of Ranitidine and Famotidine across Caco-2 Cell Monolayers , 2002, Journal of Pharmacology and Experimental Therapeutics.

[14]  P. Borst,et al.  Mammalian ABC transporters in health and disease. , 2002, Annual review of biochemistry.

[15]  J. Polli,et al.  Rational use of in vitro P-glycoprotein assays in drug discovery. , 2001, The Journal of pharmacology and experimental therapeutics.

[16]  Terry R Stouch,et al.  Progress in understanding the structure-activity relationships of P-glycoprotein. , 2002, Advanced drug delivery reviews.

[17]  A. Schinkel,et al.  Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. , 2003, Advanced drug delivery reviews.

[18]  S. Kajiji,et al.  P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists. , 2001, The Journal of pharmacology and experimental therapeutics.

[19]  Sean Ekins,et al.  Modeling of active transport systems. , 2002, Advanced drug delivery reviews.

[20]  M. Fromm,et al.  P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. , 2000, International journal of clinical pharmacology and therapeutics.

[21]  Jiunn H. Lin,et al.  Role of P-Glycoprotein in Pharmacokinetics , 2003, Clinical pharmacokinetics.

[22]  M. Borgnia,et al.  Competition of Hydrophobic Peptides, Cytotoxic Drugs, and Chemosensitizers on a Common P-glycoprotein Pharmacophore as Revealed by Its ATPase Activity (*) , 1996, The Journal of Biological Chemistry.

[23]  Lemont B. Kier,et al.  The electrotopological state: structure information at the atomic level for molecular graphs , 1991, J. Chem. Inf. Comput. Sci..

[24]  J Ferté,et al.  Analysis of the tangled relationships between P-glycoprotein-mediated multidrug resistance and the lipid phase of the cell membrane. , 2000, European journal of biochemistry.

[25]  D. Roden,et al.  The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. , 1998, The Journal of clinical investigation.

[26]  J. Beijnen,et al.  Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Igor V. Tetko,et al.  Prediction of n-Octanol/Water Partition Coefficients from PHYSPROP Database Using Artificial Neural Networks and E-State Indices , 2001, J. Chem. Inf. Comput. Sci..

[28]  Gombar Vk.  Reliable Assessment of Log P of Compounds of Pharmaceutical Relevance , 1999 .

[29]  Stephen A. Wring,et al.  Passive Permeability and P-Glycoprotein-Mediated Efflux Differentiate Central Nervous System (CNS) and Non-CNS Marketed Drugs , 2002, Journal of Pharmacology and Experimental Therapeutics.

[30]  J. Schellens,et al.  P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. , 1999, Pharmacological research.

[31]  Joseph W. Polli,et al.  Role of P-Glycoprotein on the CNS Disposition of Amprenavir (141W94), an HIV Protease Inhibitor , 1999, Pharmaceutical Research.