Potassium being the most abundant cytoplasmic cation, plays a predominant role in the ‘electrical signals of life’ where its controlled influx/efflux across the plasma membrane regulates cellular processes. Five Kv7 isoforms (Kv7.1-Kv7.5) makeup a family of ion channels that facilitate conduction of potassium ion efflux in-response to a depolarization in the transmembrane potential. Kv7.1 co-assembled with the β-auxiliary subunit KCNE1 (E1) is expressed in cardiomyocytes and is essential for cardiac function. The Kv7.2 and Kv7.3 isoforms together form heteromers within neurons and play a role in controlling excitability. Kv7.4 is expressed within cochlear hair cells and plays a role in sound amplification. Finally, the Kv7.5 channel regulates excitability within smooth muscles. Given the ubiquitous distribution of Kv7 channels and involvement in essential cellular processes, their misfunction is associated with a range of disorders including the long-QT syndrome (LQTS), epilepsy, hyperactivity, deafness, and loss of bladder control. Despite the prevalence of Kv7-associated disorders, no approved pharmaceutical interventions targeted at the channels exist. While a rich pharmacology of molecules are capable of modulating Kv7 function, they however display diverse binding sites and more importantly a lack of subtype-specificity. Ongoing experimental research within the laboratory has identified a slew of novel endogenous and exogenous compounds capable of modulating Kv7 ion channels in a state- and subtype-specific manner. Leveraging in-house electrophysiology experiments and the ongoing NAISS Large compute grant (Project ID: 2023/3-35), the laboratory made significant headway in unravelling the binding sites for these classes of compounds. (1) Endocannabinoids with an anionic head-group and lipophilic tail bind to the extracellular part of the Kv7.1 channel to augment function. (2) Phytocannabinoids specifically bind to the hydrophobic core of the Kv7.2 and Kv7.4 to augment function. (3) Estradiol-analogue hormones can specifically bind to the hydrophobic core of the Kv7.1/E1 channel to inhibit function. Based on these findings we identified other natural compounds belonging to these classes or synthetic derivatives that collectively provide a detailed pharmacological profile of how these classes of compounds modulate the Kv7 ion channels. In this project, we wish to take the next steps in developing drug molecules targeting Kv7 ion channels. To achieve this, the project envisages the use of the NAISS Large Compute grant to study the binding of a series of diverse endocannabinoids derivatives, phytocannabinoid derivatives and steroid sex hormones to Kv7 channels using molecular dynamics (MD) simulations. Through this, the project aims to unravel the chemical determinants of activity in these compounds and thereby drive the lead-development of Kv7 specific pharmaceutical interventions.