A fragment-based approach for ligand binding affinity and selectivity for the liver X receptor beta

Selective modulation of liver X receptor beta (LXRβ) has been recognized as an important approach to prevent or reverse the atherosclerotic process. In the present work, we have developed robust conformation-independent fragment-based quantitative structure–activity and structure–selectivity relationship models for a series of quinolines and cinnolines as potent modulators of the two LXR subtypes. The generated models were then used to predict the potency of an external test set and the predicted values were in good agreement with the experimental results, indicating the potential of the models for untested compounds. The final 2D molecular recognition patterns obtained were integrated to 3D structure-based molecular modeling studies to provide useful insights into the chemical and structural determinants for increased LXRβ binding affinity and selectivity.

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► Tissue-selective LXR ligands with antiatherosclerotic activity and without lipogenic activity.
► Studies allowed the identification of characteristics related to binding affinity and selectivity for LXRβ.
► 2D maps and structural studies provided insights into the determinants for the biological activity of the compounds.