Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon.

ABSTRACT: Human ether a-go-go related gene (hERG) or KV11.1 potassium channels mediate the rapid delayed rectifier current (I_Kr) in cardiac myocytes. Drug-induced inhibition of hERG channels has been implicated in the development of acquired long QT syndrome type (aLQTS) and fatal arrhythmias. Several marketed drugs have been withdrawn for this reason. Therefore, there is considerable interest in developing better tests for predicting drugs which can block the hERG channel. The drug-binding pocket in hERG channels, which lies below the selectivity filter, normally contains K⁺ ions and water molecules. In this study, we test the hypothesis that these water molecules impact drug binding to hERG. We developed 3D QSAR models based on alignment independent descriptors (GRIND)

SUBMITTER: Munawar S 

PROVIDER: S-EPMC6678931 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature