title: Predicting targets of compounds against neurological diseases using cheminformatic methodology.
abstract: 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).
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Institute of Pharmaceutical Chemistry, University of Belgrade, Vojvode Stepe 450, 11000, Belgrade, Serbia, knikolic@pharmacy.bg.ac.rs.
authors.forename: Katarina
authors.initials: K
authors.lastname: Nikolic
authors.forename: Lazaros
authors.initials: L
authors.lastname: Mavridis
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Bautista-Aguilera
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.forename: Maria
authors.initials: M
authors.lastname: do Carmo Carreiras
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rossi
authors.forename: Paola
authors.initials: P
authors.lastname: Massarelli
authors.forename: Danica
authors.initials: D
authors.lastname: Agbaba
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
authors.forename: John B O
authors.initials: JB
authors.lastname: Mitchell
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D016208:Databases, Factual; D055808:Drug Discovery; D006637:Histamine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D009422:Nervous System Diseases / Q000188:drug therapy*; D010300:Parkinson Disease / Q000188:drug therapy*; D021281:Quantitative Structure-Activity Relationship; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D008995:Monoamine Oxidase; D006637:Histamine N-Methyltransferase; D000110:Acetylcholinesterase