Application
of Quantitative Structure–Activity
Relationship Models of 5‑HT<sub>1A</sub> Receptor Binding to
Virtual Screening Identifies Novel and Potent 5‑HT<sub>1A</sub> Ligands
- Publication date
- Publisher
Abstract
The
5-hydroxytryptamine 1A (5-HT<sub>1A</sub>) 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<sub>1A</sub> receptor binding activity using data retrieved from the PDSP <i>K</i><sub>i</sub> 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 (<i>K</i><sub>i</sub>) of 2.3 nM against 5-HT<sub>1A</sub> receptor. The novel
5-HT<sub>1A</sub> actives identified with the QSAR-based virtual screening
approach could be potentially developed as novel anxiolytics or potential
antischizophrenic drugs