title: An automated docking protocol for hERG channel blockers.
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.
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Giovanni Paolo
authors.initials: GP
authors.lastname: Di Martino
authors.forename: Matteo
authors.initials: M
authors.lastname: Masetti
authors.forename: Luisa
authors.initials: L
authors.lastname: Ceccarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
mesh_terms: D001331:Automation; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011487:Protein Conformation; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D012997:Solvents