Predicting targets of compounds against neurological diseases using cheminformatic methodology
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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 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).
Nikolic , K , Mavridis , L , Bautista-Aguilera , O M , Marco-Contelles , J , Stark , H , Carreiras , M D C , Rossi , I , Massarelli , P , Agbaba , D , Ramsay , R R & Mitchell , J B O 2015 , ' Predicting targets of compounds against neurological diseases using cheminformatic methodology ' Journal of Computer-Aided Molecular Design , vol 29 , no. 2 , pp. 183-198 . DOI: 10.1007/s10822-014-9816-1
Journal of Computer-Aided Molecular Design
Copyright 2014. Springer International Publishing Switzerland. The final publication is available at Springer via http://dx.doi.org/10.1007/s10822-014-9816-1
The authors acknowledge financial support from the Scottish Universities Life Sciences Alliance (SULSA). OMBA and JMC thank MINECO (Spain) for a fellowship, and support (SAF2012-33304), respectively. KN and DA acknowledge project supported by the Ministry of Education and Science of the Republic of Serbia, Contract No. 172033. Further supports by Else Kroner-Fresenius-Stiftung, Translational Research Innovation—Pharma (TRIP), Fraunhofer-Projektgruppe fur Translationale Medizin und Pharmakologie (TMP) (to HS) and the European COST Actions BM1007, CM1103 (including STSM 10295 to KN), and CM1207 are also gratefully acknowledged.
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