This project proposes a straightforward approach to rational drug screening for ion channel-based diseases. The basic function of ion channels is to provide membrane current. In a tissue with the expression of many types of ion channels, a pathologic change in one type of channel may cause diseases. Our approach hypothesizes that the normal tissue function can be restored by compensating for the change in net current from any of the channels produced by the cell; all that is required is that a reasonable facsimile of normal net current flow be restored. We propose to apply this approach to Long Q-T Syndrome (LQTS), a condition that can cause a ventricular arrhythmia (torsades de pointe) that can lead to sudden death. The duration of the ventricular action potential (APD) depends on the balance of outward and inward currents flowing at plateau potentials. The outward currents include the delayed rectifiers IKr and IKs, while the inward currents include persistent sodium current (INaP). Specific mutations in any of these channel proteins that cause a reduction in outward current or increase in inward current are associated with congenital long QT syndrome (LQTS). There is also a much more prevalent problem called acquired LQTS (aLQTS) that is most often associated with off target effects of drugs and therefore cost the pharmaceutical industry billions of dollars and even removes from the market some compounds that could have effectively treated other diseases. To this end, we will use recent structural information concerning IKs channel activation for in silico drug screening to search for compounds with the highest probability of interacting with the IKs channel. We will apply the candidate compounds to freshly isolated guinea pig and canine cardiac ventricular myocytes to determine their effects on the ventricular action potential and the underlying ion currents in both control and LQTS conditions. The compounds that have the most favorable changes in the LQTS APD would be identified as viable candidate compounds. Our screening databases will include more than 1,500 FDA-approved small molecule drugs. If any of these FDA-approved drugs work as an IKs-enhancing compound, it should face smaller safety barriers for FDA approval. Our approach will be built on novel structural sites in the IKs channel identified by our recent work and innovative computer algorithms for molecular docking. The significance of our approach is both specific and general. Specifically if successful, candidate compounds for both congenital and acquired forms of LQTS will emerge, permitting those afflicted with the congenital form to avoid the dangers of sudden death, while allowing existing drugs or drug candidates (previous excluded for this side effect) to be made safer for clinical use. At present the various ion channels in tissues have been identified and their physiological roles defined, the structure and structure basis of function of variety of ion channels have been elucidated, and powerful computational methods have been developed. Therefore, more generally, if successful, this approach can point the way in defining how a combination of experimental studies and computer simulations can lead to rational drug development for other ion channel diseases. This new paradigm will help ion channel-targeting drug discovery be faster, cheaper, and safer and will reduce the use of animals.
This application tests the hypothesis that a combination of detailed biophysical mechanistic studies and in silico drug screening based on novel structural information can identify drug candidates that reduce the risk of arrhythmias due to either congenital or acquired LQTS. If successful, candidate compounds for LQTS will emerge, permitting those afflicted with the congenital form to avoid the dangers of sudden death, while allowing existing drugs or drug candidates (previous excluded for this side effect) to be made safer for clinical use.
| Jia, Zhiguang; Yazdani, Mahdieh; Zhang, Guohui et al. (2018) Hydrophobic gating in BK channels. Nat Commun 9:3408 |
| Hou, Panpan; Eldstrom, Jodene; Shi, Jingyi et al. (2017) Inactivation of KCNQ1 potassium channels reveals dynamic coupling between voltage sensing and pore opening. Nat Commun 8:1730 |
| Cohen, Ira S; Lin, Richard Z; Ballou, Lisa M (2017) Acquired long QT syndrome and phosphoinositide 3-kinase. Trends Cardiovasc Med 27:451-459 |
| Cohen, Ira S; Mathias, Richard T (2016) The renin-angiotensin system regulates transmural electrical remodeling in response to mechanical load. Prog Biophys Mol Biol 122:187-201 |
