Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18

Abstract

Migraine, a complex debilitating neurological disorder is strongly associated with potassium channel subfamily K member 18 (KCNK18). Research has emphasized that high levels of KCNK18 may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like migraine. In the present study, a hybrid approach of molecular docking and virtual screening were followed by pharmacophore identification and structure modeling. Screening was performed using a two-dimensional similarity search against recommended migraine drugs, keeping in view the physicochemical properties of drugs. LigandScout tool was used for exploring pharmacophore properties and designing novel molecules. Here, we report the screening of four novel compounds that have showed maximum binding affinity against KCNK18, obtained through the ZINC database, and Drug and Drug-Like libraries. Docking studies revealed that Asp-46, Ile-324, Ile-44, Gly-118, Leu-338, Val-113, and Phe-41 are critical residues for receptor–ligand interaction. A virtual screening approach coupled with docking energies and druglikeness rules illustrated that ergotamine and PB-414901692 are potential inhibitor compounds for targeting KCNK18. We propose that selected compounds may be more potent than the previously listed drug analogs based on the binding energy values. Further analysis of these inhibitors through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful for designing novel therapeutic targets to cure migraine.

Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling

“…Our study supports the notion that TRESK channels are essentially involved in pain perception in general especially under inflammatory conditions. Recently diverse drug screening approaches identified new compounds that specifically bind and modulate the activity of TRESK channels 49 50 51 suggesting TRESK to represent a promising target molecule for the treatment of severe pain disorders such as migraine.…”

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

“…These residues are located near the extracellular face of TMs 1, 2 and 4 based on a putative structural model of the TRESK channel. Additionally, these authors suggested several compounds, which might bind to this site and be useful in the treatment of migraine [90]. Whilst this approach provides an interesting potential start point for further experimental studies, it is not known whether the suggested compounds will indeed bind to the TRESK channel nor, if they do, whether they will enhance channel activity, block channel activity or have no effect.…”

The Role of TRESK in Discrete Sensory Neuron Populations and Somatosensory Processing

“…Activation of trigeminal nociceptors innervating the dural meninges likely underlies the headache phase of migraine (Weir and Cader, 2011), offering a plausible locus of action of the mutation due to the enrichment of TRESK in these afferents (Lafrenière et al, 2010). Such data is leading to increased efforts to target channel activity as an analgesic strategy (Wright et al, 2013; Bruner et al, 2014; Sehgal et al, 2014; Mathie and Veale, 2015).…”