J Chem Inf Model - Application of quantitative structure-activity relationship models of 5-HT1A receptor binding to virtual screening identifies novel and potent 5-HT1A ligands.

Tópicos

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Resumo

The 5-hydroxytryptamine 1A (5-HT1A) 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-HT1A receptor binding activity using data retrieved from the PDSP Ki 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 ?M. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential antischizophrenic drugs.

Resumo Limpo

hydroxytryptamin hta serotonin receptor attract target treat mood anxieti disord schizophrenia develop binari classif quantit structureact relationship qsar model hta receptor bind activ use data retriev pdsp ki databas predict accuraci model estim extern fold crossvalid well use addit valid set compris structur distinct compound world molecular bioactiv databas valid model use mine three major type chemic screen librari ie druglik librari gpcr target librari divers librari identifi novel comput hit five best hit class librari chosen experiment test radioligand bind assay nine hit confirm activ experiment bind affin better m activ compound lysergol divers librari show high bind affin ki nm hta receptor novel hta activ identifi qsarbas virtual screen approach potenti develop novel anxiolyt potenti antischizophren drug

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