A cell-based molecular transport simulator for pharmacokinetic prediction and cheminformatic exploration.

In the body, cell monolayers serve as permeability barriers, determining transport of molecules from one organ or tissue compartment to another. After oral drug administration, for example, transport across the epithelial cell monolayer lining the lumen of the intestine determines the fraction of drug in the gut that is absorbed by the body. By modeling passive transcellular transport properties in the presence of an apical to basolateral concentration gradient, we demonstrate how a computational, cell-based molecular transport simulator can be used to define a physicochemical property space occupied by molecules with desirable permeability and intracellular retention characteristics. Considering extracellular domains of cell surface receptors located on the opposite side of a cell monolayer as a drug's desired site of action, simulation of transcellular transport can be used to define the physicochemical properties of molecules with maximal transcellular permeability but minimal intracellular retention. Arguably, these molecules would possess very desirable features: least likely to exhibit nonspecific toxicity, metabolism, and side effects associated with high (undesirable) intracellular accumulation; and most likely to exhibit favorable bioavailability and efficacy associated with maximal rates of transport across cells and minimal intracellular retention, resulting in (desirable) accumulation at the extracellular site of action. Simulated permeability values showed good correlations with PAMPA, Caco-2, and intestinal permeability measurements, without "training" the model and without resorting to statistical regression techniques to "fit" the data. Therefore, cell-based molecular transport simulators could be useful in silico screening tools for chemical genomics and drug discovery.