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Virtual Screening Approaches to Identify Promising Multitarget-Directed Ligands for the Treatment of Autism Spectrum
Jakub Jończyk1,2, Klaudia Przybylska1, Marek Staszewski3
1Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland.
Molecules (Basel, Switzerland)
|November 27, 2024
Summary
New compounds targeting histamine H3 receptors show promise for autism spectrum disorder (ASD) treatment. These multitarget-directed ligands also interact with dopamine D2 receptors, offering potential for novel therapeutic strategies for ASD.
Area of Science:
- Neuroscience
- Pharmacology
- Computational Chemistry
Background:
- Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with limited treatment options.
- Altered neurotransmitter systems (GABAergic, glutamatergic, cholinergic, serotonergic) are implicated in ASD.
- Histamine neurotransmission's complex interactions suggest its potential role in ASD etiology.
Purpose of the Study:
- To investigate (4-piperazin-1-ylbutyl)guanidine derivatives as potential multitarget ligands for ASD.
- To explore compounds targeting histamine H3 receptors with additional activity against dopamine D2 receptors and/or cholinesterases.
Main Methods:
- Virtual screening of 32 non-imidazole histamine H3 receptor antagonists/inverse agonists.
- Integration of SwissTargetPrediction, SEA, and PPB2 tools for ligand prediction.
- Molecular docking simulations using GOLD 5.3 and Glide 7.5 software.
Main Results:
- Identified promising ligands with potential multitarget activity.
- Compounds 25 and 30 significantly blocked D2 receptor binding (>50% at 1 µM).
- Determined pKi values at the D2 receptor for compounds 25 (6.22) and 30 (6.12).
Conclusions:
- Selected (4-piperazin-1-ylbutyl)guanidine derivatives show potential as multitarget-directed ligands.
- These compounds warrant further research for developing novel ASD treatments.
- The findings support the exploration of histamine H3 receptor modulators for ASD.
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