title: Modeling Organic Anion-Transporting Polypeptide 1B1 Inhibition to Elucidate Interaction Risks in Early Drug Design.
abstract: The importance of transporter proteins for the disposition of drugs has become increasingly apparent during the past decade. A noted drug-drug interaction risk is the inhibition of organic anion-transporting polypeptides (OATPs), key transporters for the liver uptake of the widely used statins. We show here the development of a ligand-based in silico model for interaction with OATP1B1, an important representative of the OATP family. The model is based on a structural overlay of 6 known OATP1B1 inhibitors. A data set of about 150 compounds with published OATP1B1 inhibition data was compared to the resulting "transportophor," and a similarity threshold was defined to distinguish between active and inactive molecules. In addition, using a statistical model based on physicochemical properties of the compounds as prefilter was found to enhance the overall predictivity of the model (final accuracy 0.73, specificity 074, and sensitivity 0.71, based on 126 compounds). The combined model was validated using an in-house data set (accuracy, specificity, and sensitivity were 0.63, 0.59, and 0.78, respectively; 62 compounds). The model gives also a structural overlay to the most similar template enabling visualization of where a change in a given structure might reduce the interaction with the transporter.
authors.affiliation: Lead Molecular Design, S.L., Sant Cugat del Vallés, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Zamora
authors.affiliation: Drug Safety and Metabolism, AstraZeneca R&D Gothenburg, Mölndal, Sweden. Electronic address: susanne.winiwarter@astrazeneca.com.
authors.forename: Susanne
authors.initials: S
authors.lastname: Winiwarter
mesh_terms: D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003198:Computer Simulation; D016208:Databases, Factual; D015195:Drug Design; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012306:Risk
chemical_list: D002219:Carbamates; D027381:Liver-Specific Organic Anion Transporter 1; D010880:Piperidines; C503999:SLCO1B1 protein, human; C072379:repaglinide
keywords: drug interactions; molecular modeling; organic anion-transporting polypeptide transporters; structure property relationships