title: Fingerprint-based in silico models for the prediction of P-glycoprotein substrates and inhibitors.
abstract: P-Glycoprotein (P-gp, ABCB1) plays a significant role in determining the ADMET properties of drugs and drug candidates. Substrates of P-gp are not only subject to multidrug resistance (MDR) in tumor therapy, they are also associated with poor pharmacokinetic profiles. In contrast, inhibitors of P-gp have been advocated as modulators of MDR. However, due to the polyspecificity of P-gp, knowledge on the molecular basis of ligand-transporter interaction is still poor, which renders the prediction of whether a compound is a P-gp substrate/non-substrate or an inhibitor/non-inhibitor quite challenging. In the present investigation, we used a set of fingerprints representing the presence/absence of various functional groups for machine learning based classification of a set of 484 substrates/non-substrates and a set of 1935 inhibitors/non-inhibitors. Best models were obtained using a combination of a wrapper subset evaluator (WSE) with random forest (RF), kappa nearest neighbor (kNN) and support vector machine (SVM), showing accuracies >70%. Best P-gp substrate models were further validated with three sets of external P-gp substrate sources, which include Drug Bank (n = 134), TP Search (n = 90) and a set compiled from literature (n = 76). Association rule analysis explores the various structural feature requirements for P-gp substrates and inhibitors.
authors.affiliation: University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Vasanthanathan
authors.initials: V
authors.lastname: Poongavanam
authors.forename: Norbert
authors.initials: N
authors.lastname: Haider
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000465:Algorithms; D019295:Computational Biology; D062313:Databases, Pharmaceutical; D057915:Drug Substitution; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1