Development, Validation, and Use of Quantitative Structure-Activity Relationship Models of 5-Hydroxytryptamine (2B) Receptor Ligands to Identify Novel Receptor Binders and Putative Valvulopathic Compounds among Common Drugs

publication · 7 years ago
by Alexander Tropsha, Rima Hajjo, Christopher M. Grulke, Alexander Golbraikh, Vincent Setola, Xi-Ping Huang, Bryan L. Roth (University of North Carolina at Chapel Hill)
Some antipsychotic drugs are known to cause valvular heart disease by activating serotonin 5-HT2B receptors. We have developed and validated binary classification QSAR models capable of predicting potential 5-HT2B actives. The classification accuracies of the models built to discriminate 5-HT2B actives from the inactives were as high as 80% for the external test set. These models were used to screen in silico 59‚ÄČ000 compounds included in the World Drug Index, and 122 compounds were predicted as actives with high confidence. Ten of them were tested in radioligand binding assays and nine were found active, suggesting a success rate of 90%. All validated actives were then tested in functional assays, and one compound was identified as a true 5-HT2B agonist. We suggest that the QSAR models developed in this study could be used as reliable predictors to flag drug candidates that are likely to cause valvulopathy.
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