Predicting targets of compounds against neurological diseases using cheminformatic methodology
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Bautista-Aguilera, Oscar M.
Carreiras, Maria do Carmo
Ramsay, Rona R.
Mitchell, John B. O.
Article (Published version)
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Recently 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 H-3-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. Primar...y 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).
Keywords:Multi-targeted ligands / Circular fingerprints / Off-target study / ChE / MAO / Histamine H3 receptor / HMT
Source:Journal of Computer-Aided Molecular Design, 2015, 29, 2, 183-198
- Springer, Dordrecht
- EU COST Action STSM 10295
- Scottish Universities Life Sciences Alliance (SULSA)
- Else Kroner-Fresenius-Stiftung
- Translational Research Innovation-Pharma (TRIP)
- Fraunhofer-Projektgruppe fur Translationale Medizin und Pharmakologie (TMP)