Title:	Rational discovery of cannabinoid analogues targeting the Kv7 ion channels
DNr:	LiU-compute-2024-13
Project Type:	LiU Compute
Principal Investigator:	Sara Liin <sara.liin@liu.se>
Affiliation:	Linköpings universitet
Duration:	2024-03-21 – 2025-04-01
Classification:	10603
Homepage:	https://liu.se/en/employee/sarbo42
Keywords:

Abstract

The Kv7 voltage-gated potassium channels perform the essential physiological function of potassium ion efflux across the membrane. The five isoforms of the Kv7 family comprise the cardiac Kv7.1 and predominantly neuronal Kv7.2-Kv7.5. Collectively, the Kv7 channels have complex pharmacology, owing to the ability of Kv7.2-7.5 channels to form heteromers consisting of two Kv7 isoforms, such as the Kv7.2/Kv7.3 channels and co-assemble with axillary subunits such as the Kv7.1/KCNE1 channel. This has complicated drug development initiatives which aim to minimise adverse effects by targeting specific Kv7 channels. Of particular note are the Kv7.1/KCNE1, the Kv7.2/Kv7.3 and Kv7.4 channels, which are drug targets for long-QT syndrome, epilepsy and hearing loss, respectively. An interesting lead molecule for drug development is cannabidiol (CBD) which is clinical used as an anticonvulsant and is known to enhance the activity of the Kv7.2/Kv7.3 channels. Furthering this work, we recently utilized NAISS computing resources to dissect the pharmacology of CBD on the Kv7 channels (Pökl et al. 2023). We demonstrated that CBD enhanced the activity of Kv7.2–7.5 channels yet inhibited the Kv7.1 and Kv7.1/KCNE1 channels. Thus, CBD provides a novel scaffold for drug development seeking to improve its selectivity for specific Kv7 channels. The recently resolved Kv7.2 structure in complex with CBD enables rational drug development of the CBD scaffold (Ma et al. 2023). In this project, we aim to find CBD derivative compounds that are more potent than CBD and/or improve selectivity between Kv7.1/KCNE1, Kv7.2/Kv7.3 or Kv7.4 channels. Structures are available for the Kv7.4 channel, and we have previously generated homology models of the Kv7.1/KCNE1 and Kv7.2/Kv7.3 channels. To identify channel selective compounds, we have prepared a library of ~3000 commercially available CBD derivative compounds (primarily maintaining the core resorcinol ring). This library of compounds provides a range of unique chemical functional groups that may form favourable molecular interactions with specific Kv7 channels. Guided by the recent CBD bound Kv7.2 structure, molecular docking will be used to generate binding poses for the library of CBD compounds in our Kv7 channels of interest. We aim to generate a list of around 30 compounds that provide alternative molecular interaction to the selected Kv7 channels compared to CBD. We will prioritise compounds whose molecular interactions appear specific to one of the Kv7 channels. Then we will conduct molecular dynamics simulations in a membrane system to test the stability of the binding poses. Compounds with stable binding poses will be purchased and tested using electrophysiology experiments to see whether they indeed have better potency/efficacy compared to CBD. The project should help drug development initiatives by elucidating the chemical groups of CBD analogues that are essential for activity on the Kv7 channels and has the potential to identify compounds with greater subtype selectivity.