Predicting targets of compounds against neurological diseases using cheminformatic methodology
Authorized Users Only
2015
Authors
Nikolić, Katarina
Mavridis, Lazaros
Bautista-Aguilera, Oscar M.

Marco-Contelles, Jose
Stark, Holger

Carreiras, Maria do Carmo
Rossi, Ilaria
Massarelli, Paola

Agbaba, Danica

Ramsay, Rona R.

Mitchell, John B. O.

Article (Published version)

Metadata
Show full item recordAbstract
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 / HMTSource:
Journal of Computer-Aided Molecular Design, 2015, 29, 2, 183-198Publisher:
- Springer, Dordrecht
Projects:
- 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)
DOI: 10.1007/s10822-014-9816-1
ISSN: 0920-654X
PubMed: 25425329