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.
Laboratório de Química Medicinal e Computacional, Centro de Biotecnologia Molecular Estrutural, Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São-Carlense 400, 13560-970 São Carlos, SP, Brazil.
Lívia Barros
LB
Salum
Adriano Defini
AD
Andricopulo
Káthia Maria
KM
Honório
D002784:Cholesterol / Q000378:metabolism; D003198:Computer Simulation; D003327:Coronary Disease / Q000188:drug therapy; D015195:Drug Design; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008958:Models, Molecular; D008968:Molecular Conformation; D057093:Orphan Nuclear Receptors / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D013379:Substrate Specificity
D006574:Heterocyclic Compounds, 2-Ring; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D011804:Quinolines; D002784:Cholesterol; C476282:cinnoline