Virtual screening (VS) based in the common binding site for negativelycharged activators of K+ channels: A comparison with a pharmacophore-based VS.

Abstract

A master key mechanism related to the pharmacophore of negatively charged activators (NCAs) to modulate TREK, BKca and hERG potassium (K+) channels was recently described. A polypharmacological behavior of NCAs was assessed, because all NCA found could activate these three type of K+ channels. However, the role of the binding sites (BS) in the polypharmacological nature of NCAs remains unknown. In this context, the presence of structural common patterns at the BS appears to be a valid hypothesis. Residues determined experimentally as having a significant role on K+ channel-NCAs interaction were retrieved. Structural common patterns at the NCAs BS were found between TREK, BKca and hERG K+ channels using our program Geomfinder comparing by pairs. These common BS were used for a structure-based virtual screening (VS). In parallel, a pharmacophore-based VS was carried out based in the common features of the NCAs. The VS results were organized using MM-GBSA. Nineteen compounds target in silico at least two of the three types of K+ channels studied. They also accomplish two features: 1) they were found simultaneously by structure-based VS and pharmacophore-based VS; 2) all of them point their negative charge to the pore, a feature that it is mandatory for the activation of TREK, BKca and hERG K+ channelsby NCAs. These nineteen compounds will be proposed to test by means of two-electrode voltage clamp technique in the three types of K+ channels studied.