In Silico and in Vitro Assessment of OATP1B1 Inhibition in Drug Discovery.

The organic anion-transporting polypeptide 1B1 transporter belongs to the solute carrier superfamily and is highly expressed at the basolateral membrane of hepatocytes. Several clinical studies show drug-drug interactions involving OATP1B1, thereby prompting the International Transporter Consortium to label OATP1B1 as a critical transporter that can influence a compound's disposition. To examine OATP1B1 inhibition early in the drug discovery process, we established a medium-throughput concentration-dependent OATP1B1 assay.

Predicting flexible loop regions that interact with ligands: the challenge of accurate scoring.

Flexible loop regions play a critical role in the biological function of many proteins and have been shown to be involved in ligand binding. In the context of structure-based drug design, using or predicting an incorrect loop configuration can be detrimental to the study if the loop is capable of interacting with the ligand. Three protein systems, each with at least one flexible loop region in close proximity to the known binding site, were selected for loop prediction using the CorLps program; a six residue loop region from phosphoribosylglycinamide formyltransferase (GART), two nine residue loop regions from cytochrome P450 (CYP) 119, and an 11 residue loop region from enolase were selected for loop prediction.

Potentially increasing the metabolic stability of drug candidates via computational site of metabolism prediction by CYP2C9: The utility of incorporating protein flexibility via an ensemble of structures.

Cytochrome P450 enzymes are responsible for metabolizing many endogenous and xenobiotic molecules encountered by the human body. It has been estimated that 75% of all drugs are metabolized by cytochrome P450 enzymes. Thus, predicting a compound's potential sites of metabolism (SOM) is highly advantageous early in the drug development process.

Computer-aided drug design platform using PyMOL.

The understanding and optimization of protein-ligand interactions are instrumental to medicinal chemists investigating potential drug candidates. Over the past couple of decades, many powerful standalone tools for computer-aided drug discovery have been developed in academia providing insight into protein-ligand interactions. As programs are developed by various research groups, a consistent user-friendly graphical working environment combining computational techniques such as docking, scoring, molecular dynamics simulations, and free energy calculations is needed.

New computational method for prediction of interacting protein loop regions.

Flexible loop regions of proteins play a crucial role in many biological functions such as protein-ligand recognition, enzymatic catalysis, and protein-protein association. To date, most computational methods that predict the conformational states of loops only focus on individual loop regions. However, loop regions are often spatially in close proximity to one another and their mutual interactions stabilize their conformations.

Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases.

Cyclooxygenase (COX-1/COX-2)-catalyzed eicosanoid formation plays a key role in inflammation-associated diseases. Natural forms of vitamin E are recently shown to be metabolized to long-chain carboxychromanols and their sulfated counterparts. Here we find that vitamin E forms differentially inhibit COX-2-catalyzed prostaglandin E(2) in IL-1beta-stimulated A549 cells without affecting COX-2 expression, showing the relative potency of gamma-tocotrienol approximately delta-tocopherol > gamma-tocopherol >> alpha- or beta-tocopherol.