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Pharmaceuticals
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Pharmacological Strategies to Modulate Symptoms in Autism Spectrum Disorders (ASD)
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Pharmacological Strategies to Modulate Symptoms in Autism Spectrum Disorders (ASD)

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 30 November 2025 | Viewed by 1841

Special Issue Editor

Dr. Jaime Mella Raipan

E-Mail Website
Guest Editor
Instituto de Química y Bioquímica, Universidad de Valparaíso, Valparaíso, Chile
Interests: 2D-QSAR; 3D-QSAR; Hansch analysis; Free–Wilson; structure–activity relationships; CoMFA; CoMSIA; drug design; molecular docking; molecular dynamics; medicinal chemistry; heterocycles; benzimidazole; organic synthesis; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

ASD is a neurodevelopmental disorder characterized by persistent challenges in social interaction, communication, and repetitive patterns of behavior. Approximately 75 million people worldwide are affected by ASD, representing about 1% of the global population. The current prevalence of autism among children is 1 in 36. Many individuals benefit from therapeutic interventions aimed at managing co-occurring symptoms, such as anxiety, aggression, hyperactivity, and sleep disturbances. When carefully tailored to individual needs, pharmacological approaches can play a complementary role in improving quality of life.

We invite the scientific community to contribute their research to this Special Issue. We welcome submissions related to ASD, either directly or indirectly, including but not limited to, the following topics:

Synthesis and biological evaluation of new molecules targeting pathways involved in the treatment of ASD or aimed at ameliorating its symptoms.

 In-depth computational studies to better understand proteins implicated in the development of ASD.

Molecular modeling studies proposing new small-molecule ligands with a high predicted affinity for ASD-related molecular targets, such as 5-HT receptors and GABA channels, among others.

Development of novel animal, insect, cellular, or other models to study or evaluate pharmacological treatments in ASD.

Biological evaluation of well-established drugs to identify new applications for ASD treatment or improve conditions associated with this disorder.

Extensive bibliometric studies demonstrating strong correlations between autism, its causes, molecular targets, or potential pharmacological interventions.

We look forward to your valuable contributions to advancing the field toward evidence-based pharmacological approaches that support individuals with ASD and their diverse needs.

Dr. Jaime Mella Raipan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pharmacological treatment of ASD
  • neurodevelopmental disorders
  • molecular modeling and ASD
  • drug discovery for autism
  • repurposing drugs for ASD
  • 5-HT receptors
  • GABAergic system
  • TRPC6
  • mGluR5

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Published Papers (3 papers)

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Research

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20 pages, 3307 KB  
Article
Structure-Guided Discovery of Benzoic-Acid-Based TRPC6 Ligands: An Integrated Docking, MD, and MM-GBSA SAR Study: Potential Therapeutic Molecules for Autism Spectrum Disorder
by Nicolás Ignacio Silva, Gianfranco Sabadini, David Cabezas, Cristofer González, Paulina González, Jiao Luo, Cristian O. Salas, Marco Mellado, Marcos Lorca, Javier Romero-Parra and Jaime Mella
Pharmaceuticals 2025, 18(10), 1577; https://doi.org/10.3390/ph18101577 - 18 Oct 2025
Viewed by 102
Abstract
Background: TRPC6 is recognized as a therapeutically relevant cation channel, whose activation is governed by specific ligand–pocket interactions. Methods: An integrated in silico workflow was employed, comprising structure-based docking, 100-nanosecond molecular dynamics (MD) simulations, and MM-GBSA calculations. Benzoic-acid–based compounds were designed [...] Read more.
Background: TRPC6 is recognized as a therapeutically relevant cation channel, whose activation is governed by specific ligand–pocket interactions. Methods: An integrated in silico workflow was employed, comprising structure-based docking, 100-nanosecond molecular dynamics (MD) simulations, and MM-GBSA calculations. Benzoic-acid–based compounds were designed and prioritized for binding to the TRPC6 pocket, using a known literature agonist as a reference for benchmarking. Results: Within the compound series, BT11 was found to exhibit a representative interaction profile, characterized by a key hydrogen bond with Trp680 (~64% occupancy), persistent salt-bridge interactions with Lys676 and Lys698, and π–π stacking with Phe675 and Phe679. A favorable docking score (−11.45 kcal/mol) was obtained for BT11, along with a lower complex RMSD during MD simulations (0.6–4.8 Å), compared with the reference compound (0.8–7.2 Å). A reduction in solvent-accessible surface area (SASA) after ~60 ns was also observed, suggesting decreased water penetration. The most favorable binding energy was predicted for BT11 by MM-GBSA (−67.72 kcal/mol), while SOH95 also ranked highly and slightly outperformed the reference. Conclusions: These convergent computational analyses support the identification of benzoic-acid–derived chemotypes as potential TRPC6 ligands. Testable hypotheses are proposed, along with structure–activity relationship (SAR) guidelines, to inform experimental validation and guide the design of next-generation analogs. Full article
(This article belongs to the Special Issue Pharmacological Strategies to Modulate Symptoms in Autism Spectrum Disorders (ASD))
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34 pages, 8437 KB  
Article
Metagenomic Characterization of Gut Microbiota in Children with Autism Spectrum Disorder: Microbial Signatures and Modulation by Anti-Inflammatory Diet and Probiotics
by Marysol Valencia-Buitrago, Rodrigo Dias Oliveira-Carvalho, Valbert Cardoso, Jessica Triviño-Valencia, Luisa Matilde Salamanca-Duque, Vanessa Martínez-Díaz, Jovanny Zabaleta, Narmer Fernando Galeano-Vanegas and Carlos Andrés Naranjo-Galvis
Pharmaceuticals 2025, 18(9), 1376; https://doi.org/10.3390/ph18091376 - 15 Sep 2025
Viewed by 792
Abstract
Background: Autism Spectrum Disorder (ASD) is increasingly associated with alterations in gut microbiota, intestinal permeability, and immune dysregulation. However, integrative studies exploring these mechanisms in Latin American populations are lacking. Objective: To characterize gut microbiota profiles in Colombian children with ASD and evaluate [...] Read more.
Background: Autism Spectrum Disorder (ASD) is increasingly associated with alterations in gut microbiota, intestinal permeability, and immune dysregulation. However, integrative studies exploring these mechanisms in Latin American populations are lacking. Objective: To characterize gut microbiota profiles in Colombian children with ASD and evaluate the effects of two microbiota-targeted interventions, an anti-inflammatory diet and a probiotic formulation, on microbial diversity and taxonomic composition. Methods: In a two-phase study, shotgun metagenomic sequencing was performed on fecal samples from 23 children with ASD and 7 typically developing (TD) controls. In the second phase, 17 children with ASD were randomized to receive a 12-week intervention (anti-inflammatory diet, probiotics, or no intervention). Alpha diversity indices (Shannon, Pielou, and Chao1) and differential abundance analyses were conducted. Results: Compared to TD children, those with ASD showed a higher Firmicutes/Bacteroidetes ratio and a significantly increased abundance of genera such as Clostridioides, Thomasclavelia, Alistipes, and Coprococcus. The presence of functional gastrointestinal disorders (FGIDs) in ASD patients is associated with reduced microbial richness. POST-intervention, the anti-inflammatory diet group showed that no statistically significant changes in alpha diversity were observed, although a slight upward trend was noted and significant enrichment of six bacterial genera, including Moraxella and Eubacterium. The probiotic group exhibited a significant increase in Romboutsia and a decrease in Lachnospira. Cytokine–microbiota networks in ASD were fragmented and dominated by IFN-γ and MCP-1 hubs, indicating systemic immune activation. Interventions induced functional remodeling: The anti-inflammatory diet increased the number of beneficial genera (Eubacterium, Adlercreutzia) and shifted networks toward positive correlations involving IL-8 and MIP-1β. Probiotics increased Romboutsia, reduced Lachnospira, and restructured networks with regulatory cytokines (SDF-1α, Eotaxin) and SCFA-producing taxa (Blautia, Roseburia). Conclusions: Children with ASD in Colombia displayed distinct microbial profiles characterized by pro-inflammatory taxa and altered richness. Both the anti-inflammatory diet and probiotics produced compositional shifts in the gut microbiota, although global changes in diversity were limited. These findings support the potential of microbiota-targeted nutritional strategies for ASD and underscore the need for precision interventions tailored to specific clinical and microbial phenotypes. Full article
(This article belongs to the Special Issue Pharmacological Strategies to Modulate Symptoms in Autism Spectrum Disorders (ASD))
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Review

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32 pages, 1789 KB  
Review
The Emerging Role of Phosphodiesterase Inhibitors in Fragile X Syndrome and Autism Spectrum Disorder
by Shilu Deepa Thomas, Hend Abdulaziz Mohammed, Mohammad I. K. Hamad, Murat Oz, Yauhen Statsenko and Bassem Sadek
Pharmaceuticals 2025, 18(10), 1507; https://doi.org/10.3390/ph18101507 - 8 Oct 2025
Viewed by 610
Abstract
Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders marked by deficits in communication and social interaction, often accompanied by anxiety, seizures, and intellectual disability. FXS, the most common monogenic cause of ASD, results from silencing of the FMR1 gene [...] Read more.
Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders marked by deficits in communication and social interaction, often accompanied by anxiety, seizures, and intellectual disability. FXS, the most common monogenic cause of ASD, results from silencing of the FMR1 gene and consequent loss of FMRP, a regulator of synaptic protein synthesis. Disruptions in cyclic nucleotide (cAMP and cGMP) signaling underlie both ASD and FXS contributing to impaired neurodevelopment, synaptic plasticity, learning, and memory. Notably, reduced cAMP levels have been observed in platelets, lymphoblastoid cell lines and neural cells from FXS patients as well as Fmr1 KO and dfmr1 Drosophila models, linking FMRP deficiency to impaired cAMP regulation. Phosphodiesterase (PDE) inhibitors, which prevent the breakdown of cAMP and cGMP, have emerged as promising therapeutic candidates due to their ability to modulate neuronal signaling. Several PDE isoforms—including PDE2A, PDE4D, and PDE10A—have been implicated in ASD, and FXS, as they regulate pathways involved in synaptic plasticity, cognition, and social behavior. Preclinical and clinical studies show that PDE inhibition modulates neuroplasticity, neurogenesis, and neuroinflammation, thereby ameliorating autism-related behaviors. BPN14770 (a PDE4 inhibitor) has shown promising efficacy in FXS patients while cilostazol, pentoxifylline, resveratrol, and luteolin have showed improvements in children with ASD. However, challenges such as isoform-specific targeting, optimal therapeutic window, and timing of intervention remain. Collectively, these findings highlight PDE inhibition as a novel therapeutic avenue with the potential to restore cognitive and socio-behavioral functions in ASD and FXS, for which effective targeted treatments remain unavailable. Full article
(This article belongs to the Special Issue Pharmacological Strategies to Modulate Symptoms in Autism Spectrum Disorders (ASD))
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