Characterization of binding site of closed-state KCNQ1 potassium channel by homology modeling, molecular docking, and pharmacophore identification.
This investigation was performed to assess the importance of interaction in the binding of blockers to KCNQ1 potassium using molecular modeling. This work could be considered made up by three main steps: (1) the construction of closed-state structure of KCNQ1 through homology modeling; (2) the automated docking of three blockers: IKS-142, L-735821, and BMS-IKS, using DOCK program; (3) the generation and validation of pharmacophore for KCNQ1 ligands using Catalyst/HypoGen. The obtained results highlight the hydrophobic or aromatic residues involved in S6 transmembrane domain and the base of the pore helix of KCNQ1, confirming the mutagenesis data and pharmacophore model, and giving new suggestions for the rational design of novel KCNQ1 ligands.
Du
Lü-Pei
LP
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Li
Min-Yong
MY
Tsai
Keng-Chang
KC
You
Qi-Dong
QD
Xia
Lin
L
D000595:Amino Acid Sequence; D001569:Benzodiazepines / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C115921:L 735821; D008024:Ligands; D024642:Potassium Channels, Voltage-Gated; D001569:Benzodiazepines