Learn More
Long-term exposure to antivirals is associated with serious cellular toxicity to the kidney and other tissues. Organic anion transporters (OATs) are believed to mediate the cellular uptake, and hence cytotoxicity, of many antivirals. However, a systematic in vitro and ex vivo analysis of interactions between these compounds with various OAT isoforms has(More)
Organic anion transporters (OATs, SLC22) interact with a remarkably diverse array of endogenous and exogenous organic anions. However, little is known about the structural features that determine their substrate selectivity. We examined the substrate binding preferences and transport function of olfactory organic anion transporter, Oat6, in comparison with(More)
We present the cellular quantitative structure-activity relationship (cell-QSAR) concept that adapts ligand-based and receptor-based 3D-QSAR methods for use with cell-level activities. The unknown intracellular drug disposition is accounted for by the disposition function (DF), a model-based, nonlinear function of a drug's lipophilicity, acidity, and other(More)
To alleviate the problems in the receptor-based design of metalloprotein ligands due to inadequacies in the force-field description of coordination bonds, a four-tier approach was devised. Representative ligand-metalloprotein interaction energies are obtained by subsequent application of (1) docking with metal-binding-guided selection of modes, (2)(More)
Design of selective ligands for closely related targets is becoming one of the most important tasks in the drug development. New tools, more precise than fast scoring functions and less demanding than sophisticated Free Energy Perturbation methods, are necessary to help accomplish this goal. The methods of intermediate complexity, characterizing individual(More)
The development of covariate models within the population modeling program like NONMEM is generally a time-consuming and non-trivial task. In this study, a fast procedure to approximate the change in objective function values of covariate-parameter models is presented and evaluated. The proposed method is a first-order conditional estimation (FOCE)-based(More)
Structure-based predictions of binding affinities of ligands binding to proteins by coordination bonds with transition metals, covalent bonds, and bonds involving charge re-distributions are hindered by the absence of proper force fields. This shortcoming affects all methods which use force-field-based molecular simulation data on complex formation for(More)
The pregnane X receptor (PXR) regulates the expression of genes involved in xenobiotic metabolism and transport. In vitro methods to screen for PXR agonists are used widely. In the current study, computational models for human PXR activators and PXR nonactivators were developed using recursive partitioning (RP), random forest (RF), and support vector(More)
The hASBT (human apical Na(+)-dependent bile acid transporter) constitutes a key target of anti-hypercholesterolaemic therapies and pro-drug approaches; physiologically, hASBT actively reclaims bile acids along the terminal ileum via Na(+) co-transport. Previously, TM (transmembrane segment) 7 was identified as part of the putative substrate permeation(More)
PURPOSE We applied in silico methods to automatically classify drugs according to the Biopharmaceutics Drug Disposition Classification System (BDDCS). MATERIALS AND METHODS Models were developed using machine learning methods including recursive partitioning (RP), random forest (RF) and support vector machine (SVM) algorithms with ChemDraw, clogP, polar(More)