Hologram quantitative structure-activity relationships for a series of farnesoid X receptor activators.
The farnesoid X receptor (FXR) is an attractive drug target for the development of novel therapeutic agents for the treatment of dyslipidemia and cholestasis. Hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent FXR activators originated from natural product-like libraries. A training set containing 82 compounds served to establish the models. The best HQSAR model was generated using atoms, bonds, connections, chirality, and donor and acceptor as fragment distinction and fragment size default (4-7) with six components. The model was used to predict the potency of 20 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results. The final HQSAR model and the information obtained from HQSAR 2D contribution maps should be useful for the design of novel FXR ligands having improved potency.
Honorio
Kathia M
KM
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.
Garratt
Richard C
RC
Andricopulo
Adriano D
AD
D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism*; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D012015:Reference Standards; D013256:Steroids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D004268:DNA-Binding Proteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated