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.

Keywords: KCNK18; TRESK; bioinformatics; migraine; modeling and docking; pharmacoinformatics; virtual screening.

Figure 1

KCNK18 structure predicted by utilizing PDB ID 3UKM. Abbreviations: KCNK18, potassium channel subfamily K member 18; PDB ID, Protein Data Bank identification.

Figure 2

Two-dimensional structures of investigated drugs. Notes: (A) acetaminophen; (B) almotriptan; (C) aspirin; (D) diclofenac; (E) ibuprofen; (F) rizatriptan; (G) lasmiditan; (H) telcagepant; (I) ergotamine.

Figure 3

Novel molecules in two-dimensional structures. Notes: (A) PB-408318540; (B) PB-415019010; (C) PB-414901730; (D) PB-414901692.

Figure 4

All the selected ligands bind at same binding pocket in KCNK18. Abbreviation: KCNK18, potassium channel subfamily K member 18.

Figure 5

Binding pocket and interacting residues of novel analyzed molecules. Notes: Binding site pattern of (A) PB-408318540; (B) PB-415019010; (C) PB-414901730; (D) PB-414901692 with KCNK18. Ligand is shown in green color. Binding residues of KCNK18 are shown in black wires.