title: Development of an in silico model for predicting efflux substrates in Caco-2 cells.
abstract: P-glycoprotein (P-gp) is an ATP dependent efflux transporter protein that has been demonstrated to play a critical role in affecting the absorption, metabolism, elimination and toxicity (ADMET) characteristics of a large number of marketed drugs. Therefore, it is important to evaluate whether or not compounds of interest are likely to interact with P-gp and/or other efflux transporters. An in silico efflux substrate (potential substrate of P-gp and or other transporters) classification model has been developed based on in vitro bi-directional Caco-2 cell permeability and five descriptors, using 14 marketed drugs and >100 discovery compounds synthesized at Bristol-Myers Squibb PRI. The model suggests that efflux substrates tend to contain electron deficient aromatic rings, are highly branched, and most contain tertiary nitrogen. This model demonstrated approximately 80% predictability of both non-substrates and substrates from a training set of 125 compounds. For a validation set of 46 compounds the predictability was approximately 72% for non-substrates and approximately 89% for substrates. The model has the potential to be used both as a filter for library designs to identify potential efflux substrates in early discovery as well as a primary screening methodology to identify the efflux substrate potential of drug candidates.
authors.affiliation: Bristol-Myers Squibb Company PRI, Route 206 & Provinceline Road, P.O. Box 4000, Princeton, NJ 08543, USA. Litai.zhang@bms.com
authors.forename: Litai
authors.initials: L
authors.lastname: Zhang
authors.forename: Praveen V
authors.initials: PV
authors.lastname: Balimane
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Johnson
authors.forename: Saeho
authors.initials: S
authors.lastname: Chong
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations