Identification of Possible Binding Sites for the CFTR Pore Blocker, GlyH-101

Abstract

The last decade has seen the discovery by means of high throughput screening of a wide range of small-molecule modulators of the CFTR chloride channel. These compounds act by altering anion conduction, channel gating and/or trafficking of the CFTR protein. However, binding sites for these molecules on CFTR or other cellular constituents have yet to be identified. GlyH-101 is a CFTR modulator that blocks the channel by entering from the extracellular side and binding to a site within the pore. In an effort to identify possible GlyH-101 binding sites within the pore of the CFTR channel, we applied the small-molecule docking program, “Glide” (Schrodinger, Inc.), to a series of molecular models of CFTR, derived by means of molecular dynamics simulation from a homology model based on the prokaryotic ABC transporter, Sav1866 (Dawson and Locher, Nature 443: 180-185, 2006; Alexander et al., Biochemistry in press, 2009).