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PLoS One. 2013 Dec 18;8(12):e84510. doi: 10.1371/journal.pone.0084510. eCollection 2013.

A linear combination of pharmacophore hypotheses as a new tool in search of new active compounds--an application for 5-HT1A receptor ligands.

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Medicinal Chemistry Department, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Medicinal Pharmacology and Toxicology, Department of Medicinal Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
Department of Cell Biology, National Medicines Institute, Warsaw, Poland.


This study explores a new approach to pharmacophore screening involving the use of an optimized linear combination of models instead of a single hypothesis. The implementation and evaluation of the developed methodology are performed for a complete known chemical space of 5-HT1AR ligands (3616 active compounds with K i < 100 nM) acquired from the ChEMBL database. Clusters generated from three different methods were the basis for the individual pharmacophore hypotheses, which were assembled into optimal combinations to maximize the different coefficients, namely, MCC, accuracy and recall, to measure the screening performance. Various factors that influence filtering efficiency, including clustering methods, the composition of test sets (random, the most diverse and cluster population-dependent) and hit mode (the compound must fit at least one or two models from a final combination) were investigated. This method outmatched both single hypothesis and random linear combination approaches.

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