title: Modeling the hERG potassium channel in a phospholipid bilayer: Molecular dynamics and drug docking studies.
abstract: The hERG potassium channel has recently been a matter of extensive studies both at experimental and computational levels, because of its possible involvement in the potentially lethal drug-induced long QT syndrome. In this context, in the absence of an experimentally determined 3D structure, to acquire a detailed description of the channel pore and an understanding of atomic determinants for drug binding is of enormous interest at both academic and industrial levels. To contribute to this aim, we first built the open and closed states of the channel by homology modeling techniques, and then submitted both channel models to ns-time-scale MD simulations in explicit membrane. An in-depth analysis of the dynamical behavior of the channel pore with particular attention to the cavity volume was carried out. Finally, using hERG conformations coming from MD simulations, docking experiments were performed to identify a possible binding mode for the most potent hERG channel blocker so far known, the antihistaminic drug astemizole. We show that the combined use of MD and docking is suitable to identify a possible binding mode of drugs in a fairly good agreement with experiments. Moreover, the exploitation of MD snapshots in the docking experiments allowed us to capture some induced-fit effects related to the side chain conformations of Tyr652 and Phe656, which are residues playing a pivotal role in the hERG drug binding.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, via Belmeloro, 6 I-40126 Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Masetti
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
mesh_terms: D000595:Amino Acid Sequence; D016589:Astemizole / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D008051:Lipid Bilayers; D010743:Phospholipids; D016589:Astemizole