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.

Di Martino G. P., Masetti M., Ceccarini L., Cavalli A., Recanatini M. (2013). An automated docking protocol for HERG channel blockers. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 53, 159-175 [10.1021/ci300326d].

An automated docking protocol for HERG channel blockers.

DI MARTINO, GIOVANNI PAOLO;MASETTI, MATTEO;CECCARINI, LUISA;CAVALLI, ANDREA;RECANATINI, MAURIZIO
2013

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.
2013
Di Martino G. P., Masetti M., Ceccarini L., Cavalli A., Recanatini M. (2013). An automated docking protocol for HERG channel blockers. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 53, 159-175 [10.1021/ci300326d].
Di Martino G. P.; Masetti M.; Ceccarini L.; Cavalli A.; Recanatini M.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/133627
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