Molecular Modeling of Drug–Transporter Interactions—An International Transporter Consortium Perspective

Membrane transporters play diverse roles in the pharmacokinetics and pharmacodynamics of small-molecule drugs. Understanding the mechanisms of drug-transporter interactions at the molecular level is, therefore, essential for the design of drugs with optimal therapeutic effects. This white paper examines recent progress, applications, and challenges of molecular modeling of membrane transporters, including modeling techniques that are centered on the structures of transporter ligands, and those focusing on the structures of the transporters. The goals of this article are to illustrate current best practices and future opportunities in using molecular modeling techniques to understand and predict transporter-mediated effects on drug disposition and efficacy.Membrane transporters from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate the cellular uptake, efflux, and homeostasis of many essential nutrients and significantly impact the pharmacokinetics of drugs; further, they may provide targets for novel therapeutics as well as facilitate prodrug approaches. Because of their often broad substrate selectivity they are also implicated in many undesirable and sometimes life-threatening drug–drug interactions (DDIs).^5,6.