, Volume 30, Issue 4, pp 996-1007
Date: 27 Dec 2012

Human Intestinal Transporter Database: QSAR Modeling and Virtual Profiling of Drug Uptake, Efflux and Interactions

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Abstract

Purpose

Membrane transporters mediate many biological effects of chemicals and play a major role in pharmacokinetics and drug resistance. The selection of viable drug candidates among biologically active compounds requires the assessment of their transporter interaction profiles.

Methods

Using public sources, we have assembled and curated the largest, to our knowledge, human intestinal transporter database (>5,000 interaction entries for >3,700 molecules). This data was used to develop thoroughly validated classification Quantitative Structure-Activity Relationship (QSAR) models of transport and/or inhibition of several major transporters including MDR1, BCRP, MRP1-4, PEPT1, ASBT, OATP2B1, OCT1, and MCT1.

Results

QSAR models have been developed with advanced machine learning techniques such as Support Vector Machines, Random Forest, and k Nearest Neighbors using Dragon and MOE chemical descriptors. These models afforded high external prediction accuracies of 71–100% estimated by 5-fold external validation, and showed hit retrieval rates with up to 20-fold enrichment in the virtual screening of DrugBank compounds.

Conclusions

The compendium of predictive QSAR models developed in this study can be used for virtual profiling of drug candidates and/or environmental agents with the optimal transporter profiles.