Referenced in: none

Automatically associated channels: Kv11.1

Title: An automated docking protocol for hERG channel blockers.

Authors: Giovanni Paolo Di Martino, Matteo Masetti, Luisa Ceccarini, Andrea Cavalli, Maurizio Recanatini

Journal, date & volume: J Chem Inf Model, 2013 Jan 28 , 53, 159-75

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23259741

Abstract
A docking protocol aimed at obtaining a consistent qualitative and quantitative picture of binding for a series of hERG channel blockers is presented. To overcome the limitations experienced by standard procedures when docking blockers at hERG binding site, we designed a strategy that explicitly takes into account the conformations of the channel, their possible intrinsic symmetry, and the role played by the configurational entropy of ligands. The protocol was developed on a series of congeneric sertindole derivatives, allowing us to satisfactorily explain the structure-activity relationships for this set of blockers. In addition, we show that the performance of structure-based models relying on multiple-receptor conformations statistically increases when the protein conformations are chosen in such a way as to capture relevant structural features at the binding site. The protocol was then successfully applied to a series of structurally unrelated blockers.