A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration. Zhang, X.; Shedden, K.; and Rosania, G. Mol. Pharm., 3(6):704--716, 2006.
A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration [link]Paper  doi  abstract   bibtex   
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.
@article{Zhang:2006aa,
	Abstract = {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.},
	Author = {Zhang, X. and Shedden, Kerby and Rosania, G.R.},
	Date-Added = {2007-12-11 17:01:03 -0500},
	Date-Modified = {2007-12-11 17:01:03 -0500},
	Doi = {10.1021/mp060046k},
	Journal = {Mol. Pharm.},
	Keywords = {Biological Availability; Biological Transport; Caco-2 Cells; Cell Membrane Permeability; Chemistry, Analytical; Computer Simulation; Diffusion; Humans; Informatics; Intestinal Absorption; Models, Biological; Models, Theoretical; Pharmacokinetics},
	Local-Url = {file://localhost/Users/rguha/Documents/articles/mp060046k.pdf},
	Number = {6},
	Owner = {rajarshi},
	Pages = {704--716},
	Pmid = {17140258},
	Timestamp = {2007.04.16},
	Title = {A Cell-Based Molecular Transport Simulator for Pharmacokinetic Prediction and Cheminformatic Exploration},
	Url = {http://dx.doi.org/10.1021/mp060046k},
	Volume = {3},
	Year = {2006},
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