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.
Gombar
Vijay K
VK
Department of Drug Metabolism and Pharmacokinetics, Metabolic and Viral Diseases' Center of Excellence for Drug Discovery, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
Polli
Joseph W
JW
Humphreys
Joan E
JE
Wring
Stephen A
SA
Serabjit-Singh
Cosette S
CS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier; D002460:Cell Line; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003198:Computer Simulation; D004285:Dogs; D006860:Hydrogen Bonding; D016014:Linear Models; D008956:Models, Chemical; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations