Application of Quantitative Structure–Activity Relationship Models of 5-HT(1A) Receptor Binding to Virtual Screening Identifies Novel and Potent 5-HT(1A) Ligands

[Image: see text] The 5-hydroxytryptamine 1A (5-HT(1A)) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure–activity relationship (QSAR) models of 5-HT(1A) receptor binding activity using data retrieved from the PDSP K(i) database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 μM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (K(i)) of 2.3 nM against 5-HT(1A) receptor. The novel 5-HT(1A) actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs.