# In Silico Methods for the Discovery of Kv7.2/7.3 Channels Modulators: A Comprehensive Review

## TL;DR

This review discusses how computer-based methods are being used to find new drugs that target Kv7.2/7.3 channels, which are linked to brain disorders like epilepsy.

## Contribution

The paper provides a comprehensive overview of in silico approaches for designing Kv7.2/7.3 channel modulators, highlighting recent computational and medicinal chemistry advances.

## Key findings

- In silico methods have become essential for designing Kv7.2/7.3 agonists due to recent structural insights.
- Computational techniques are helping identify new chemotypes to replace the withdrawn drug retigabine.
- Structure-function relationships are guiding the development of more effective and selective Kv7 modulators.

## Abstract

The growing interest in Kv7.2/7.3 agonists originates from the involvement of these channels in several brain hyperexcitability disorders. In particular, Kv7.2/7.3 mutants have been clearly associated with epileptic encephalopathies (DEEs) as well as with a spectrum of focal epilepsy disorders, often associated with developmental plateauing or regression. Nevertheless, there is a lack of available therapeutic options, considering that retigabine, the only molecule used in clinic as a broad-spectrum Kv7 agonist, has been withdrawn from the market in late 2016. This is why several efforts have been made both by both academia and industry in the search for suitable chemotypes acting as Kv7.2/7.3 agonists. In this context, in silico methods have played a major role, since the precise structures of different Kv7 homotetramers have been only recently disclosed. In the present review, the computational methods used for the design of Kv.7.2/7.3 small molecule agonists and the underlying medicinal chemistry are discussed in the context of their biological and structure-function properties.