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Carriers, Channels, Receptors, and Enzymes: Protein Targets of New Synthetic and Natural Compounds

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

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 8124

Special Issue Editors

Dr. Annalisa De Palma

E-Mail Website
Guest Editor
Department of Biosciences, Biotechnologies and Enviroment, NIBA University of Bari “Aldo Moro”, Via E. Orabona, 4, 70125 Bari, Italy
Interests: mitochondrial carrier; a-glucosidase inhibitors; AChE inhibitors; neurotoxicity; butyrylcholinesterase inhibitors
Dr. Anna Spagnoletta

E-Mail Website
Guest Editor
ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Department of Sustainability, Trisaia Research Center, 75026 Rotondella, Italy
Interests: mitochondria; protein purification; antioxidant activity; biomolecules extraction; agricultural waste valorization; novel food
Special Issues, Collections and Topics in MDPI journals
Dr. Giovanni Lentini

E-Mail Website
Guest Editor
Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy
Interests: medicinal chemistry; drug discovery; chirality
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins are biomolecules playing a key role in biochemical and physiological processes, especially as carriers, channels, receptors and enzymes. There are also various links between the malfunction or even absence of any of these functions and several human diseases, including diabetes, metabolic syndrome, cardiovascular and neurodegenerative diseases, infectious diseases, and cancer. Therefore, scientific research is committed to designing and synthesizing or extracting from natural sources new bioactive compounds that have protein biomolecules as pharmacological targets to develop innovative treatments of human pathologies. This Special Issue aims to collect and publish original research articles and reviews on the design, synthesis, and development of new bioactive molecules or on natural compounds as drug candidates targeting carriers, channels, receptors, and enzymes.

In particular, we invite scientists focused on organic chemistry, medicinal chemistry, food chemistry, chemical biology, and biotechnology to report studies of synthetic and natural compounds ranging from the design and synthesis to their pharmacological evaluation in vivo or in vitro and computational modeling.

We very much look forward to your contributions.

Dr. Annalisa De Palma
Dr. Anna Spagnoletta
Prof. Dr. Giovanni Lentini
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

  • carrier
  • channel
  • receptor
  • enzyme
  • drug design
  • synthesis
  • biological evaluation
  • inhibitors
  • bioactive compounds
  • cell metabolism
  • mitochondria
  • human pathology

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Published Papers (6 papers)

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Research

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21 pages, 5086 KiB  
Article
Insights into the Involvement of TRPA1 Channels in the Neuro-Inflammatory Machinery of Trigeminal Neuralgia
by Chiara Demartini, Rosaria Greco, Anna Maria Zanaboni, Miriam Francavilla, Sara Facchetti, Cristina Nativi and Cristina Tassorelli
Molecules 2025, 30(9), 1884; https://doi.org/10.3390/molecules30091884 - 23 Apr 2025
Viewed by 171
Abstract
Antagonism of transient receptor potential ankyrin type-1 (TRPA1) channels counteracts the experimentally induced trigeminal neuralgia (TN) pain. TRPA1 channels activated/sensitized by inflammatory stimuli can modulate glial cell activity, a driving force for pathological pain. Additionally, the evidence of a link between TRPA1 and [...] Read more.
Antagonism of transient receptor potential ankyrin type-1 (TRPA1) channels counteracts the experimentally induced trigeminal neuralgia (TN) pain. TRPA1 channels activated/sensitized by inflammatory stimuli can modulate glial cell activity, a driving force for pathological pain. Additionally, the evidence of a link between TRPA1 and the inflammatory-related Toll-like receptors 4 (TLR4) and 7 (TLR7) highlights the potential of the TRPA1-blocking strategy to reduce pain and inflammation in TN. In this study, we aimed to further investigate the putative involvement of TRPA1 channels in the inflammatory pathways following the development of TN. We focused on the possible modulation of glial activity after TRPA1 blockade and the crosstalk of TRPA1 with TLR7 and TLR4. In a rat model of TN, based on chronic constriction injury of the infraorbital nerve, the impact of TRPA1 antagonism through ADM_12 treatment was assessed following the onset of mechanical allodynia (26 days post-surgery). The evaluation of central and peripheral inflammatory mediators (by rt-PCR and ELISA) and immunofluorescence staining of glial expression in the trigeminal nucleus caudalis was investigated using plasma samples and areas related to the trigeminal system (trigeminal ganglion and areas containing the trigeminal nucleus caudalis). Compared to sham-operated rats, the TN-like animals showed significant increases in the number of microglial and astroglial cells in the trigeminal nucleus caudalis, with higher and lower protein plasma levels of pro-inflammatory and anti-inflammatory cytokines, respectively. Additionally, in the trigeminal-related areas, TN-like animals showed significantly higher gene expression levels of TLR4, TLR7, miR-let-7b, and high-mobility group box-1. TRPA1 antagonism reverted all the observed alterations in TN-like rats in the trigeminal-related areas and plasma except microglial cell number in the trigeminal nucleus caudalis. The findings suggest that, in addition to their known involvement in the nociceptive pathway, TRPA1 channels may also play a direct or indirect role in pain-related inflammation, through the activation of TLR4- and TLR7-mediated pathways at the neuronal and glial levels. Full article
(This article belongs to the Special Issue Carriers, Channels, Receptors, and Enzymes: Protein Targets of New Synthetic and Natural Compounds)
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17 pages, 1921 KiB  
Article
Use of Ionic Liquids in the Enzymatic Synthesis of Structured Docosahexaenoic Acid Lyso-Phospholipids
by Ernestina Garcia-Quinto, Jose M. Guisan and Gloria Fernandez-Lorente
Molecules 2025, 30(3), 728; https://doi.org/10.3390/molecules30030728 - 6 Feb 2025
Viewed by 671
Abstract
Recent studies have shown that DHA supplementation in the form of phospholipids effectively increases DHA levels in the brain, including DHA lysophospholipids. This research explores a method to produce DHA lysophosphatidylcholine (DHA-LPC) using lipases and phospholipases immobilized on Immobeads-C18 with maximal enzyme loading. [...] Read more.
Recent studies have shown that DHA supplementation in the form of phospholipids effectively increases DHA levels in the brain, including DHA lysophospholipids. This research explores a method to produce DHA lysophosphatidylcholine (DHA-LPC) using lipases and phospholipases immobilized on Immobeads-C18 with maximal enzyme loading. The esterification of glycerophosphatidylcholine (GPC) and DHA was studied with ionic liquids as alternatives to traditional solvents, with 1-methyl-3-octylimidazolium tetrafluoroborate (MOIM-BF4) providing the highest yield due to its ability to increase the solubility of GPC. The reaction parameters were modified to establish a molar ratio of GPC to DHA of 1/10. A maximum DHA-LPC yield of 80% was achieved in 48 h, with a formation rate of 20.06 (mg/mL.h) × g. The Quara® LowP biocatalyst (QlowP-C18) maintained 100% activity during the first three cycles and produced 788 mg of DHA lysophospholipid. The use of 50% MOIM-BF4 improved the stability of the biocatalyst, and NMR confirmed that the product was the sn1-DHA-LPC isomer. Full article
(This article belongs to the Special Issue Carriers, Channels, Receptors, and Enzymes: Protein Targets of New Synthetic and Natural Compounds)
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18 pages, 6414 KiB  
Article
Modulatory Effect of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) on the 2-Oxoglutarate Mitochondrial Carrier
by Anna Spagnoletta, Daniela Valeria Miniero, Nicola Gambacorta, Francesca Oppedisano, Anna De Grassi, Orazio Nicolotti, Ciro Leonardo Pierri and Annalisa De Palma
Molecules 2024, 29(21), 5154; https://doi.org/10.3390/molecules29215154 - 31 Oct 2024
Viewed by 1067
Abstract
The 2-oxoglutarate carrier (OGC), pivotal in cellular metabolism, facilitates the exchange of key metabolites between mitochondria and cytosol. This study explores the influence of NADPH on OGC transport activity using proteoliposomes. Experimental data revealed the ability of NADPH to modulate the OGC activity, [...] Read more.
The 2-oxoglutarate carrier (OGC), pivotal in cellular metabolism, facilitates the exchange of key metabolites between mitochondria and cytosol. This study explores the influence of NADPH on OGC transport activity using proteoliposomes. Experimental data revealed the ability of NADPH to modulate the OGC activity, with a significant increase of 60% at 0.010 mM. Kinetic analysis showed increased Vmax and a reduction in Km for 2-oxoglutarate, suggesting a direct regulatory role. Molecular docking pointed to a specific interaction between NADPH and cytosolic loops of OGC, involving key residues such as K206 and K122. This modulation was unique in mammalian OGC, as no similar effect was observed in a plant OGC structurally/functionally related mitochondrial carrier. These findings propose OGC as a responsive sensor for the mitochondrial redox state, coordinating with the malate/aspartate and isocitrate/oxoglutarate shuttles to maintain redox balance. The results underscore the potential role of OGC in redox homeostasis and its broader implications in cellular metabolism and oxidative stress responses. Full article
(This article belongs to the Special Issue Carriers, Channels, Receptors, and Enzymes: Protein Targets of New Synthetic and Natural Compounds)
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25 pages, 1638 KiB  
Review
The Role of Brain-Derived Neurotrophic Factor as an Essential Mediator in Neuronal Functions and the Therapeutic Potential of Its Mimetics for Neuroprotection in Neurologic and Psychiatric Disorders
by Tadahiro Numakawa and Ryutaro Kajihara
Molecules 2025, 30(4), 848; https://doi.org/10.3390/molecules30040848 - 12 Feb 2025
Cited by 2 | Viewed by 1888
Abstract
Among neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5), BDNF has been extensively studied for its physiological role in cell survival and synaptic regulation in the central nervous system’s (CNS’s) neurons. BDNF binds to TrkB (a [...] Read more.
Among neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5), BDNF has been extensively studied for its physiological role in cell survival and synaptic regulation in the central nervous system’s (CNS’s) neurons. BDNF binds to TrkB (a tyrosine kinase) with high affinity, and the resulting downstream intracellular signaling cascades play crucial roles in determining cell fate, including neuronal differentiation and maturation of the CNS neurons. It has been well demonstrated that the downregulation/dysregulation of the BDNF/TrkB system is implicated in the pathogenesis of neurologic and psychiatric disorders, such as Alzheimer’s disease (AD) and depression. Interestingly, the effects of BDNF mimetic compounds including flavonoids, small molecules which can activate TrkB-mediated signaling, have been extensively investigated as potential therapeutic strategies for brain diseases, given that p75NTR, a common neurotrophin receptor, also contributes to cell death under a variety of pathological conditions such as neurodegeneration. Since the downregulation of the BDNF/TrkB system is associated with the pathophysiology of neurodegenerative diseases and psychiatric disorders, understanding how alterations in the BDNF/TrkB system contribute to disease progression could provide valuable insight for the prevention of these brain diseases. The present review shows recent advances in the molecular mechanisms underlying the BDNF/TrkB system in neuronal survival and plasticity, providing critical insights into the potential therapeutic impact of BDNF mimetics in the pathophysiology of brain diseases. Full article
(This article belongs to the Special Issue Carriers, Channels, Receptors, and Enzymes: Protein Targets of New Synthetic and Natural Compounds)
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21 pages, 4272 KiB  
Review
Analysis of Structures of SARS-CoV-2 Papain-like Protease Bound with Ligands Unveils Structural Features for Inhibiting the Enzyme
by Ann Varghese, Jie Liu, Bailang Liu, Wenjing Guo, Fan Dong, Tucker A. Patterson and Huixiao Hong
Molecules 2025, 30(3), 491; https://doi.org/10.3390/molecules30030491 - 23 Jan 2025
Viewed by 1201
Abstract
The COVID-19 pandemic, driven by the novel coronavirus SARS-CoV-2, has drastically reshaped global health and socioeconomic landscapes. The papain-like protease (PLpro) plays a critical role in viral polyprotein cleavage and immune evasion, making it a prime target for therapeutic intervention. Numerous compounds have [...] Read more.
The COVID-19 pandemic, driven by the novel coronavirus SARS-CoV-2, has drastically reshaped global health and socioeconomic landscapes. The papain-like protease (PLpro) plays a critical role in viral polyprotein cleavage and immune evasion, making it a prime target for therapeutic intervention. Numerous compounds have been identified as inhibitors of SARS-CoV-2 PLpro, with many characterized through crystallographic studies. To date, over 70 three-dimensional (3D) structures of PLpro complexed ligands have been deposited in the Protein Data Bank, offering valuable insight into ligand-binding features that could aid the discovery and development of effective COVID-19 treatments targeting PLpro. In this study, we reviewed and analyzed these 3D structures, focusing on the key residues involved in ligand interactions. Our analysis revealed that most inhibitors bind to PLpro’s substrate recognition sites S3/S4 and SUb2. While these sites are highly attractive and have been extensively explored, other potential binding regions, such as SUb1 and the Zn(II) domain, are less explored and may hold untapped potential for future COVID-19 drug discovery and development. Our structural analysis provides insights into the molecular features of PLpro that could accelerate the development of novel therapeutics targeting this essential viral enzyme. Full article
(This article belongs to the Special Issue Carriers, Channels, Receptors, and Enzymes: Protein Targets of New Synthetic and Natural Compounds)
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15 pages, 5358 KiB  
Review
Decoding the κ Opioid Receptor (KOR): Advancements in Structural Understanding and Implications for Opioid Analgesic Development
by Zoe Li, Ruili Huang, Menghang Xia, Nancy Chang, Wenjing Guo, Jie Liu, Fan Dong, Bailang Liu, Ann Varghese, Aasma Aslam, Tucker A. Patterson and Huixiao Hong
Molecules 2024, 29(11), 2635; https://doi.org/10.3390/molecules29112635 - 3 Jun 2024
Viewed by 2280
Abstract
The opioid crisis in the United States is a significant public health issue, with a nearly threefold increase in opioid-related fatalities between 1999 and 2014. In response to this crisis, society has made numerous efforts to mitigate its impact. Recent advancements in understanding [...] Read more.
The opioid crisis in the United States is a significant public health issue, with a nearly threefold increase in opioid-related fatalities between 1999 and 2014. In response to this crisis, society has made numerous efforts to mitigate its impact. Recent advancements in understanding the structural intricacies of the κ opioid receptor (KOR) have improved our knowledge of how opioids interact with their receptors, triggering downstream signaling pathways that lead to pain relief. This review concentrates on the KOR, offering crucial structural insights into the binding mechanisms of both agonists and antagonists to the receptor. Through comparative analysis of the atomic details of the binding site, distinct interactions specific to agonists and antagonists have been identified. These insights not only enhance our understanding of ligand binding mechanisms but also shed light on potential pathways for developing new opioid analgesics with an improved risk-benefit profile. Full article
(This article belongs to the Special Issue Carriers, Channels, Receptors, and Enzymes: Protein Targets of New Synthetic and Natural Compounds)
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