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Predicting targets of compounds against neurological diseases using cheminformatic methodology

AuthorsNikolic, Katarina; Mavridis, L.; Bautista-Aguilera, Oscar M.; Marco-Contelles, José ; Stark, H.; do Carmo Carreiras, María; Rossi, I.; Massarelli, P.; Agbaba, Danica; Ramsay, Rona R.; Mitchell, J. B. O.
Circular fingerprints
Off-target study
Histamine H3 receptor
Multi-targeted ligands
Issue Date2015
PublisherKluwer Academic Publishers
CitationJournal of Computer-Aided Molecular Design 29: 183- 198 (2015)
AbstractRecently developed multi-targeted ligands are novel drug candidates able to interact with monoamine oxidase A and B; acetylcholinesterase and butyrylcholinesterase; or with histamine N-methyltransferase and histamine H3-receptor (H3R). These proteins are drug targets in the treatment of depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease. A probabilistic method, the Parzen-Rosenblatt window approach, was used to build a >predictor> model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Molecular structures were represented based on the circular fingerprint methodology. The same approach was used to build a >predictor> model from the DrugBank dataset to determine the main pharmacological groups of the compound. The study of off-target interactions is now recognised as crucial to the understanding of both drug action and toxicology. Primary pharmaceutical targets and off-targets for the novel multi-target ligands were examined by use of the developed cheminformatic method. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. The cheminformatic targets identifications were in agreement with four 3D-QSAR (H3R/D1R/D2R/5-HT2aR) models and by in vitro assays for serotonin 5-HT1a and 5-HT2a receptor binding of the most promising ligand (71/MBA-VEG8).
Identifiersdoi: 10.1007/s10822-014-9816-1
issn: 0920-654X
e-issn: 1573-4951
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