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

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, ofte...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2024-07, Vol.29 (13), p.3234
Main Authors: Stagno, Claudio, Mancuso, Francesca, Ciaglia, Tania, Ostacolo, Carmine, Piperno, Anna, Iraci, Nunzio, Micale, Nicola
Format: Article
Language:English
Subjects:
Animals
antiepileptic
Computer Simulation
Convulsions & seizures
Crystal structure
Drug Discovery - methods
Epilepsy
Genes
Hormones
Humans
KCNQ
KCNQ2 Potassium Channel - chemistry
KCNQ2 Potassium Channel - genetics
KCNQ2 Potassium Channel - metabolism
KCNQ3 Potassium Channel - antagonists & inhibitors
KCNQ3 Potassium Channel - chemistry
KCNQ3 Potassium Channel - genetics
KCNQ3 Potassium Channel - metabolism
Kinases
Kv7
molecular docking
molecular dynamics
Mutation
Neurological disorders
Physiology
Potassium
potassium channel
Proteins
Structure-Activity Relationship
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Summary: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options, considering that retigabine, the only molecule used in clinic as a broad-spectrum Kv7 agonist, has been withdrawn from the market in late 2016.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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules29133234