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

Turpo-Peqqueña A.G.; Valencia-Arce R.J.; Del-Carpio-Carrazco F.L.; Quispe-Ppacco D.J.; Carbajal-Llerena P.F.; Loza-Chipa H.R.; Vásquez-Macedo A.S.; Gómez B. · International Journal of Molecular Sciences (2025) · DOI: 10.3390/ijms262010188

Resumen

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 (CK1 (Formula presented.)) 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 CK1 (Formula presented.) using molecular docking, molecular dynamics simulations, and binding free energy calculations. Among them, BZH exhibited the most stable interaction with CK1 (Formula presented.) ((Formula presented.) 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 CK1 (Formula presented.) inhibitors for future experimental validation in the treatment of ALS.

Instituciones: Universidad Nacional de San Agustín de Arequipa; Universidad Católica de Santa María