Study of Molecular Docking, Physicochemical and Pharmacokinetic Properties of GSK-3β Inhibitors

Aims: Alzheimer disease (AD) affects people aged 65 to 90 years and is the most prevalent neurodegenerative disease in the world. The deposition of β-amyloid peptide forming the amyloid plaques as well as neurofibrillary tangles deposition due to hyperphosphorylation of tau protein are the major cause of the disease in addition to the deficit of the neurotransmitter acetylcholine in the synaptic gap. Among the treatments for AD are acetylcholinesterase, beta-secretase and Glycogen Synthase Kinase-3β (GSK-3β) inhibitors. GSK-3β has been associated with all primary abnormalities of AD, because it interacts with the different components of the amyloid plaques production system and participates in the phosphorylation of tau protein. This regulates and stabilizes the microtubules in axons of the neurons of the Central Nervous System (CNS). The present study aimed to propose three novel candidates for inhibitors of GSK-3β.
Place and Duration of Study: Laboratory of Modeling and Computational Chemistry (LMCC) at Federal University of Amapá (UNIFAP), Macapá, Brazil, between November 2014 and March 2015.
Methodology: First, we used the crystal structure of GSK-3β enzyme deposited in the the Protein Data Bank (PDB) (PDB ID: 3Q3B – at 2.7 Å resolution). Then, we selected 50 inhibitors reported and available in the database BindingDB. Docking simulations were subsequently carried out using the AutoDock Vina 1.5.6 software. In sequence, a pharmacophore perception calculation was performed as well as and pharmacokinetic properties calculations. Finally, new proposals of GSK-3β inhibitors candidates were designed, considering in addition potential biological activity and synthetic accessibility as well as.
Results: In the study of physical and chemical parameters, most of the compounds violated no more than two parameters of the Lipinski’s Rule of five, indicating suitable oral absorption. Along of the docking simulations, 22 inhibitors showed strong interaction with the amino acid residues of the enzyme active site (hydrogen bond and hydrophobic interactions). Along of the pharmacophore perception calculation, 30 molecules lined up with four pharmacophore points: two aromatic rings and two hydrogen bond acceptor groups (in the case, pyrimidine group). Along the prediction of pharmacokinetics, the most of the potential GSK-3β inhibitors showed good permeability of Caco2 and MDCK cells, high absorption in the human intestine and weak binding to plasma proteins, but only two ones showed absorption in the blood brain barrier. The three proposals of GSK-3β inhibitor candidates indicate biological activity for GSK-3β, as well as having average synthetic accessibility.
Conclusion: This current study reveals three new promising compounds with in silico GSK-3β inhibitory activity. Therefore, further studies of quantitative structure-activity relationship as are necessary to investigate how the chemical structures of these molecules affect their biological potency and binding affinity for GSK-3β enzyme, and thus, selecting potential drug candidates for synthesis and biological testing.