The primary focus of this laboratory is on developing small-molecule probes for members of the inward rectifier family of potassium (Kir) channels, which play key physiological roles in cardiac, neuronal, endocrine and epithelial cell function. An emerging body of genetic evidence suggests that certain members of the Kir channel family represent novel drug targets for hypertension, cardiac arrhythmias, secretory diarrhea and pain. However, it has not been possible to assess their therapeutic potential due to the lack of drug-like molecules capable of modulating the function of specific Kir channels in vivo.
Over the last three years, the Denton Laboratory has worked closely with researchers in Vanderbilt’s High-throughput Screening Center for GPCRs, Ion Channels and Transporters, and the Center for Accelerated Probe Development to deploy a National Institutes of Health-funded drug discovery campaign directed toward the founding member of the Kir channel family and putative diuretic target Kir1.1. From a primary screen of 225,000 small molecules, and secondary screens of a 300-member “focus library” of Kir1.1 channel antagonists, some of the first selective of Kir1.1, Kir3.X and Kir7.1 channels have been discovered. Medicinal chemistry is being used to refine the potency and selectivity of these compounds.
Recently, the investigators rationally designed a highly selective Kir1.1 channel inhibitor that will be used in animal studies to assess the therapeutic potential of Kir1.1 as a diuretic target. Molecular modeling, X-ray structure-guided mutagenesis and electrophysiology are being used to define the atomic features of small-molecule binding sites in Kir channels. This work is expected to provide critically-needed pharmacological tools with which to probe the structure, integrative physiology and therapeutic potential of clinically-important inward rectifying potassium channels.