PLS and shape-based similarity analysis of maleimides--GSK-3 inhibitors.

CONTEXT: Glycogen synthase kinase-3 (GSK-3) overactivity was correlated with several pathologies including type 2 diabetes mellitus, Alzheimer's disease, cancer, inflammation, obesity, etc.

OBJECTIVE

The aim of the current investigation was to model the inhibitory activity of maleimide derivatives--inhibitors of GSK-3, to evaluate the impact of alignment on statistical performances of the Quantitative Structure-Activity Relationship (QSAR) and the effect of the template on shape-similarity--binding affinity relationship.

MATERIALS AND

METHODS

Dragon descriptors were used to generate Projection to Latent Structures (PLS) models in order to identify the structural prerequisites of maleimides to inhibit GSK-3. Additionally, shape/volume structural analysis of binding site interactions was evaluated.

RESULTS

Reliable statistics R(2)(Y(CUM)) = 0.938/0.920, Q((2)(Y)(CUM)) = 0.866/0.838 for aligned and alignment free QSAR models and significant (Pearson, Kendall and Spearman) correlations between shape/volume similarity and affinities were obtained.

DISCUSSION AND

CONCLUSIONS

The crucial structural features modulating the activity of maleimides include topology, charge, geometry, 2D autocorrelations, 3D-MoRSE as well as shape/volume and molecular flexibility.