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Recent Advances in CNS Drug Discovery
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Recent Advances in CNS Drug Discovery

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 13216

Special Issue Editors

Prof. Dr. Fernanda Borges

E-Mail Website
Guest Editor
Centro de Investigação em Química da Universidade do Porto (CIQUP), Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169–007 Porto, Portugal
Interests: drug discovery; nanomedicine; ADME-Tox; neurodegenerative; infectious diseases; antioxidants
Special Issues, Collections and Topics in MDPI journals
Dr. Sofia Benfeito

E-Mail Website
Guest Editor
CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
Interests: medicinal chemistry; organic chemistry; neurodegenerative diseases; bioactive compounds and drug design; toxicology
Special Issues, Collections and Topics in MDPI journals
Dr. Daniel Chavarria

E-Mail Website
Guest Editor
CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
Interests: drug discovery; multitarget-directed ligands; neurodegenerative diseases; infectious diseases; biological and toxicological screenings
Special Issues, Collections and Topics in MDPI journals
Dr. Pedro Soares

E-Mail Website
Guest Editor
CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
Interests: medicinal chemistry; chemical biology; neurodegenerative diseases; evaluation of ADMET properties; biophysical screening

Special Issue Information

Dear Colleagues,

Neurological diseases are a major cause of death and disability worldwide. With the increased human life expectancy and demographic ageing, the prevalence of neurological diseases is expected to rise dramatically and impose social and economic burdens. However, the discovery of novel and innovative pharmacological treatments for CNS diseases remains a huge medical need.

The development of CNS drugs is a long and difficult process, presenting numerous challenges from both biological and chemical perspectives. In the present Special Issue, we welcome the submission of research articles on the design, synthesis, and biological and toxicological screening of novel chemical entities targeting neurological diseases, as well as the development of drug delivery systems for the CNS. High-quality reviews in the field are also welcomed.

Prof. Dr. Fernanda Borges
Dr. Sofia Benfeito
Dr. Daniel Chavarria
Dr. Pedro Soares
Guest Editors

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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

  • Alzheimer’s disease
  • Parkinson’s disease
  • Amyloid lateral sclerosis
  • Schizophrenia Stroke
  • Brain cancer
  • Blood–brain barrier
  • Depression
  • Drug discovery
  • Single-target- and multi-target-directed ligands
  • Dopamine
  • Histamine
  • Serotonin
  • Mitochondrial dysfunction
  • Apoptosis
  • Oxidative stress
  • Neuroinflammation
  • Protein aggregation
  • Protein dysregulation
  • Transcription factors
  • Nanosystems/nanomaterials

Published Papers (4 papers)

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Research

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18 pages, 11821 KiB  
Article
Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer’s Disease Treatment through Rigidification Strategy
by Cédric Lecoutey, Rémi Legay, Audrey Davis, Jana Sopková-de Oliveira Santos, Patrick Dallemagne and Christophe Rochais
Molecules 2021, 26(9), 2536; https://doi.org/10.3390/molecules26092536 - 26 Apr 2021
Cited by 4 | Viewed by 2759
Abstract
The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer’s disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic [...] Read more.
The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer’s disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT4 receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT4R and 5-HT6R and this study led to the description of novel ligand targeting both AChE and 5-HT6R. Full article
(This article belongs to the Special Issue Recent Advances in CNS Drug Discovery)
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16 pages, 2186 KiB  
Article
A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model
by Julia Post, Vanessa Kogel, Anja Schaffrath, Philipp Lohmann, N. Jon Shah, Karl-Josef Langen, Dieter Willbold, Antje Willuweit and Janine Kutzsche
Molecules 2021, 26(6), 1590; https://doi.org/10.3390/molecules26061590 - 13 Mar 2021
Cited by 7 | Viewed by 3129
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in the brain stem and spinal cord. The cause is unknown, but an increasing amount of evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in the brain stem and spinal cord. The cause is unknown, but an increasing amount of evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe a treatment study demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of ALS (SOD1*G93A). Mice were treated intraperitoneally for four weeks with RD2RD2 vs. placebo. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both the brain stem and lumbar spinal cord, but also in a rescue of neurons in the motor cortex. RD2RD2 treatment was able to slow progression of the disease phenotype, especially the motor deficits, to an extent that during the four weeks treatment duration, no significant progression was observed in any of the motor experiments. Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS. Full article
(This article belongs to the Special Issue Recent Advances in CNS Drug Discovery)
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18 pages, 4469 KiB  
Article
Androgen Receptor Binding Category Prediction with Deep Neural Networks and Structure-, Ligand-, and Statistically Based Features
by Alfonso T. García-Sosa
Molecules 2021, 26(5), 1285; https://doi.org/10.3390/molecules26051285 - 26 Feb 2021
Cited by 2 | Viewed by 2332
Abstract
Substances that can modify the androgen receptor pathway in humans and animals are entering the environment and food chain with the proven ability to disrupt hormonal systems and leading to toxicity and adverse effects on reproduction, brain development, and prostate cancer, among others. [...] Read more.
Substances that can modify the androgen receptor pathway in humans and animals are entering the environment and food chain with the proven ability to disrupt hormonal systems and leading to toxicity and adverse effects on reproduction, brain development, and prostate cancer, among others. State-of-the-art databases with experimental data of human, chimp, and rat effects by chemicals have been used to build machine-learning classifiers and regressors and to evaluate these on independent sets. Different featurizations, algorithms, and protein structures lead to different results, with deep neural networks (DNNs) on user-defined physicochemically relevant features developed for this work outperforming graph convolutional, random forest, and large featurizations. The results show that these user-provided structure-, ligand-, and statistically based features and specific DNNs provided the best results as determined by AUC (0.87), MCC (0.47), and other metrics and by their interpretability and chemical meaning of the descriptors/features. In addition, the same features in the DNN method performed better than in a multivariate logistic model: validation MCC = 0.468 and training MCC = 0.868 for the present work compared to evaluation set MCC = 0.2036 and training set MCC = 0.5364 for the multivariate logistic regression on the full, unbalanced set. Techniques of this type may improve AR and toxicity description and prediction, improving assessment and design of compounds. Source code and data are available on github. Full article
(This article belongs to the Special Issue Recent Advances in CNS Drug Discovery)
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Review

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28 pages, 897 KiB  
Review
Neurodegeneration in Multiple Sclerosis: Symptoms of Silent Progression, Biomarkers and Neuroprotective Therapy—Kynurenines Are Important Players
by Dániel Sandi, Zsanett Fricska-Nagy, Krisztina Bencsik and László Vécsei
Molecules 2021, 26(11), 3423; https://doi.org/10.3390/molecules26113423 - 05 Jun 2021
Cited by 19 | Viewed by 4162
Abstract
Neurodegeneration is one of the driving forces behind the pathogenesis of multiple sclerosis (MS). Progression without activity, pathopsychological disturbances (cognitive impairment, depression, fatigue) and even optic neuropathy seems to be mainly routed in this mechanism. In this article, we aim to give a [...] Read more.
Neurodegeneration is one of the driving forces behind the pathogenesis of multiple sclerosis (MS). Progression without activity, pathopsychological disturbances (cognitive impairment, depression, fatigue) and even optic neuropathy seems to be mainly routed in this mechanism. In this article, we aim to give a comprehensive review of the clinical aspects and symptomology, radiological and molecular markers and potential therapeutic targets of neurodegeneration in connection with MS. As the kynurenine pathway (KP) was evidenced to play an important role in the pathogenesis of other neurodegenerative conditions (even implied to have a causative role in some of these diseases) and more and more recent evidence suggest the same central role in the neurodegenerative processes of MS as well, we pay special attention to the KP. Metabolites of the pathway are researched as biomarkers of the disease and new, promising data arising from clinical evaluations show the possible therapeutic capability of KP metabolites as neuroprotective drugs in MS. Our conclusion is that the kynurenine pathway is a highly important route of research both for diagnostic and for therapeutic values and is expected to yield concrete results for everyday medicine in the future. Full article
(This article belongs to the Special Issue Recent Advances in CNS Drug Discovery)
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