Searching potential GSK-3β inhibitors from marine sources using atomistic simulations

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• Glycogen synthase kinase-3 beta (GSK-3β) is a key target in cancer therapy.
• Natural compounds are increasingly explored for their therapeutic potential.
• Identifying novel inhibitors for GSK-3β is crucial for cancer prevention.

Purpose of the Study:

• To investigate marine compounds as potential inhibitors of GSK-3β.
• To evaluate the ligand-binding affinity of selected marine compounds to GSK-3β.
• To predict the toxicity of these compounds for therapeutic applications.

Main Methods:

• Atomistic simulations were employed to study ligand-binding affinity.
• Molecular docking and steered molecular dynamics (MD) simulations were used.
• Perturbation simulations assessed compound potency, and toxicity predictions were performed.

Main Results:

• Four marine compounds—xanalteric acid I, chaunolidone A, macrolactin V, and aspergiolide A—showed potential to inhibit GSK-3β.
• These compounds demonstrated favorable binding affinities and potency.
• Toxicity predictions indicated a low toxicity profile for the identified compounds.

Conclusions:

• Xanalteric acid I, chaunolidone A, macrolactin V, and aspergiolide A are potential natural inhibitors of GSK-3β.
• These compounds may serve as a basis for developing new anti-cancer therapeutics.
• Specific amino acid residues (Ile62, Val135, Pro136, Arg141, Lys183, Gln185, Asn186, Asp200) are critical for GSK-3β binding.