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Developing new kinds of assays and approaches for exploiting and improving current assay techniques.

In addition to designing, synthesizing, and testing candidate molecules for their therapeutic potential, investigators in the Drug Discovery Division also develop new kinds of assays or devise approaches for exploiting and improving current assay techniques.

In close collaboration with other scientists at the Institute, Johns Hopkins University, and NIH, we are developing assays to drive rapid decision-making for drug discovery projects. From high-throughput fluorescent readouts to liquid chromatography/mass spectrometry (LC/MS) methods, as well as design of custom expression cell lines, we have the tools to quickly evaluate new drug candidates.

High Throughput Assays
High-throughput assays. To assess many compounds quickly, which is critical in the initial phases of testing newly synthesized molecules, we rely on high-throughput assays. Important goals of assay development are to standardize the assay and be able to use it repeatedly and reproducibly. Molecular biologists within the Drug Discovery Division develop and perform high-throughput assays in a 96-well or 384-well microplate format to screen new molecules prepared by the medicinal chemists.

Ion Channel Electrophysiology
An essential component of the process of evaluating a candidate compound is understanding how it might affect the activity of ion channels, which are essential to neuronal function. In collaboration with our colleagues at the Lieber Institute and Johns Hopkins University, we use traditional patch-clamp and high-throughput electrophysiology assays to monitor the effects of novel compounds on ion channel activity. One current project, for example, is to identify the effects of novel compounds on the hERG K+channel encoded by the 3.1 isoform of the KCNH2 gene.

Mass Spectrometry
Metabolism and Pharmacokinetics. To treat schizophrenia, it would be ideal to design a compound that patients could take orally once a day, and that achieves a critical balance in terms of its ability to enter the brain and avoid rapid clearance. We begin this phase of testing with assays designed to measure the metabolism and pharmacokinetics of a candidate molecule. Starting from in vitro measurements of the stability of new compounds in human and rodent liver microsomes, we can select compounds for further in vivo testing to evaluate oral bioavailability and half-life.

Most systemically administered drugs do not enter the brain readily because of the tight epithelial cell junctions (the blood-brain barrier) as well as efflux transporters. Therefore, one challenge is getting a drug into the brain. Generally, drugs that are able to enter the brain readily need to be less than a certain weight, have moderate lipophilicity, and no more than two hydrogen-bond donors. We can estimate a compound’s propensity to penetrate the brain first by in vitro assays of transporter susceptibility, and then by evaluating in vivo drug levels in plasma and brain.