Predicting targets of compounds against neurological diseases using cheminformatic methodology

J Comput Aided Mol Des. 2015 Feb;29(2):183-98. doi: 10.1007/s10822-014-9816-1. Epub 2014 Nov 26.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Databases, Factual
  • Drug Discovery
  • Histamine N-Methyltransferase / chemistry
  • Histamine N-Methyltransferase / metabolism
  • Humans
  • Ligands
  • Monoamine Oxidase / chemistry
  • Monoamine Oxidase / metabolism
  • Nervous System Diseases / drug therapy*
  • Parkinson Disease / drug therapy*
  • Quantitative Structure-Activity Relationship
  • Receptor, Serotonin, 5-HT2A / chemistry
  • Receptor, Serotonin, 5-HT2A / metabolism

Substances

  • Ligands
  • Receptor, Serotonin, 5-HT2A
  • Monoamine Oxidase
  • Histamine N-Methyltransferase
  • Acetylcholinesterase