# Inhibition of Casein Kinase 1δ as a Novel Therapeutic Strategy for Amyotrophic Lateral Sclerosis: A Theoretical Study

## TL;DR

This theoretical study explores CK1δ inhibition as a potential treatment for ALS, identifying three promising compounds for further testing.

## Contribution

The study introduces BZH, IMF, and BIP as novel CK1δ inhibitors for ALS treatment through computational analysis.

## Key findings

- BZH showed the most stable interaction with CK1δ with a binding energy of −46.53±1.94 kcal/mol.
- IMF and BIP demonstrated good oral absorption and blood–brain barrier crossing potential.
- All compounds were classified as toxicity Class IV, indicating moderate risk.

## Abstract

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease characterized by the degeneration of motor neurons and the pathological accumulation of phosphorylated TDP-43. Casein kinase one delta (CK1δ) has been identified as a key regulator of this aberrant phosphorylation, making it a promising therapeutic target. In this theoretical study, 26 structurally diverse compounds were evaluated against CK1δ using molecular docking, molecular dynamics simulations, and binding free energy calculations. Among them, BZH exhibited the most stable interaction with CK1δ (−46.53±1.94 kcal/mol). An inverse correlation was observed between theoretical affinity and experimental IC50 values, supporting the predictive validity of the computational approach. Pharmacokinetic analysis indicated that IMF and BIP show good oral absorption and the ability to cross the blood–brain barrier. At the same time, the toxicological profile classified all compounds in toxicity Class IV (moderate risk). Additionally, dynamic migration toward an alternative pocket was observed during simulation, highlighting the importance of considering protein flexibility in drug design. This study proposes BZH, IMF, and BIP as promising CK1δ inhibitors for future experimental validation in the treatment of ALS.