Computational Modeling of Drugs for Alzheimer’s Disease: Design of Serotonin 5-HT6 Antagonists

  • Ádám A. Kelemen
  • Stefan Mordalski
  • Andrzej J. Bojarski
  • György M. KeserűEmail author
Part of the Neuromethods book series (NM, volume 132)


The 5-hydroxytryptamine receptor 6 (5-HT6R) represents one of the most avowed targets for alleviating cognitive, learning, and memory deficits related to Alzheimer’s disease (AD). Ligand- and structure-based computational modeling methods serve as main tools at the initial stages of drug discovery projects to underlie and to understand small molecule targeting of the receptor. Here, we describe the currently known 5-HT6R antagonists in clinical trials and at discovery stages. We analyze existing ligand-based information and disposable pharmacophore models, quantitative structure-activity relationship methods, usable crystal structure templates, homology models, and molecular docking approaches. Our goal is to provide the reader with guidelines on how to utilize the existing knowledge and ligand- and structure-based methods for the design of new 5-HT6R antagonists and to highlight advantages and limitations of corresponding approaches and computational modeling tools in the field of 5-HT6R drug design.

Key words

5-Hydroxytryptamine receptor 6 Alzheimer’s disease Pharmacophore modeling Quantitative structure-activity relationship Bioisosteres Homology modeling Molecular dynamics Site-directed mutagenesis Molecular docking 



The authors participate in the European Cooperation in Science and Technology (COST) Action CM1207 – GPCR-Ligand Interactions, Structures, and Transmembrane Signalling: a European Research Network (GLISTEN). This work was supported by the National Brain Research Program KTIA-NAP-13-1-2013-0001. The study was partially supported by the grant OPUS 2014/13/B/NZ7/02210 from the Polish National Science Centre.


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Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Ádám A. Kelemen
    • 1
  • Stefan Mordalski
    • 2
  • Andrzej J. Bojarski
    • 2
  • György M. Keserű
    • 1
    Email author
  1. 1.Medicinal Chemistry Research Group, Research Center for Natural Sciences, Hungarian Academy of SciencesBudapestHungary
  2. 2.Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of SciencesKrakowPoland

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