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Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 23042

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Dr. Gabriella Guerrini

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Dipartimento NEUROFARBA, Università degli Studi di Firenze, Via U. Schiff, 6, 50019 Polo Scientifico, Sesto Fiorentino, Firenze, Italy
Interests: heterocyclic nitrogen compounds; pyrazolo condensed compounds; synthesis; GABAA receptor subtype; human neutrophil elastase inhibitors; medicinal chemistry
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Dr. Maria P. Giovannoni

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Co-Guest Editor

Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
Interests: medicinal chemistry; organic synthesis; heterocycles; GABAA subtype receptors; HNE inhibitors; FPR
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The targeting of ion channels represents a strategy for the treatment of several pathologies since they are responsible for the ion fluxes across membranes and contribute to maintain cellular functions in central and peripheral tissues. The ion channels include two principal types of membrane proteins:

The ligand-gated ion channel (LGICs), opened by neurotransmitters or ligands that bind the orthosteric or allosteric sites, involved in the overall fast synaptic transmission in the nervous system;
Voltage-gated ion channels, opened or closed by a change in the electrical gradient across the membrane.

Ion channels are very intriguing targets, and the development of new techniques elucidating the structures of these channels (e.g., cryo-EM) contributes to the design of new potential therapeutic agents for the treatment of neurological and neurodegenerative diseases, cancer, metabolic syndrome and pain.

This Special Issue, titled ‘Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation’, aims to collect contributions in the drug design, molecular modelling, pharmacological investigation and therapeutic applications of ion channel ligands.

Dr. Maria P. Giovannoni
Dr. Gabriella Guerrini
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

LGIC
voltage-gated ion channel
other ion channels
biological studies
diseases
molecular modeling
drug design
synthesis

Related Special Issue

Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation 2.0 in International Journal of Molecular Sciences (2 articles)

Published Papers (11 papers)

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Editorial

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4 pages, 178 KiB

Open AccessEditorial

Ion Channels as a Therapeutic Target: Drug Design and Pharmacological Investigation

by Gabriella Guerrini and Maria Paola Giovannoni

Int. J. Mol. Sci. 2024, 25(1), 171; https://doi.org/10.3390/ijms25010171 - 22 Dec 2023

Viewed by 548

Abstract

This Special Issue intends to illustrate the novelties in the field of ion channels [...] Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

Research

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19 pages, 8135 KiB

Open AccessArticle

The Effect of CaV1.2 Inhibitor Nifedipine on Chondrogenic Differentiation of Human Bone Marrow or Menstrual Blood-Derived Mesenchymal Stem Cells and Chondrocytes

by Ilona Uzieliene, Daiva Bironaite, Rokas Miksiunas, Edvardas Bagdonas, Raminta Vaiciuleviciute, Ali Mobasheri and Eiva Bernotiene

Int. J. Mol. Sci. 2023, 24(7), 6730; https://doi.org/10.3390/ijms24076730 - 04 Apr 2023

Cited by 2 | Viewed by 1672

Abstract

Cartilage is an avascular tissue and sensitive to mechanical trauma and/or age-related degenerative processes leading to the development of osteoarthritis (OA). Therefore, it is important to investigate the mesenchymal cell-based chondrogenic regenerating mechanisms and possible their regulation. The aim of this study was to investigate the role of intracellular calcium (iCa²⁺) and its regulation through voltage-operated calcium channels (VOCC) on chondrogenic differentiation of mesenchymal stem/stromal cells derived from human bone marrow (BMMSCs) and menstrual blood (MenSCs) in comparison to OA chondrocytes. The level of iCa²⁺ was highest in chondrocytes, whereas iCa²⁺ store capacity was biggest in MenSCs and they proliferated better as compared to other cells. The level of CaV1.2 channels was also highest in OA chondrocytes than in other cells. CaV1.2 antagonist nifedipine slightly suppressed iCa²⁺, Cav1.2 and the proliferation of all cells and affected iCa²⁺ stores, particularly in BMMSCs. The expression of the CaV1.2 gene during 21 days of chondrogenic differentiation was highest in MenSCs, showing the weakest chondrogenic differentiation, which was stimulated by the nifedipine. The best chondrogenic differentiation potential showed BMMSCs (SOX9 and COL2A1 expression); however, purposeful iCa²⁺ and VOCC regulation by blockers can stimulate a chondrogenic response at least in MenSCs. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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19 pages, 3026 KiB

Open AccessArticle

GABA_A Receptor Modulators with a Pyrazolo[1,5-a]quinazoline Core: Synthesis, Molecular Modelling Studies and Electrophysiological Assays

by Letizia Crocetti, Gabriella Guerrini, Fabrizio Melani, Claudia Vergelli, Maria Paola Mascia and Maria Paola Giovannoni

Int. J. Mol. Sci. 2022, 23(21), 13032; https://doi.org/10.3390/ijms232113032 - 27 Oct 2022

Cited by 3 | Viewed by 1141

Abstract

As a continuation of our study in the GABA_A receptor modulators field, we report the design and synthesis of new 8-chloropyrazolo[1,5-a]quinazoline derivatives. Molecular docking studies and the evaluation of the ‘Proximity Frequencies’ (exploiting our reported model) were performed on all the final compounds (3, 4, 6a–c, 7a,b, 8, 9, 12a–c, 13a,b, 14–19) to predict their profile on the α1β2γ2-GABA_AR subtype. Furthermore, to verify whether the information coming from this virtual model was valid and, at the same time, to complete the study on this series, we evaluated the effects of compounds (1–100 µM) on the modulation of GABA_A receptor function through electrophysiological techniques on recombinant α1β2γ2L-GABA_A receptors expressed in Xenopus laevis oocytes. The matching between the virtual prediction and the electrophysiological tests makes our model a useful tool for the study of GABA_A receptor modulators. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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24 pages, 8925 KiB

Open AccessArticle

In Silico Evaluation of Hexamethylene Amiloride Derivatives as Potential Luminal Inhibitors of SARS-CoV-2 E Protein

by Pouria H. Jalily, Horia Jalily Hasani and David Fedida

Int. J. Mol. Sci. 2022, 23(18), 10647; https://doi.org/10.3390/ijms231810647 - 13 Sep 2022

Cited by 2 | Viewed by 1757

Abstract

The coronavirus E proteins are small membrane proteins found in the virus envelope of alpha and beta coronaviruses that have a high degree of overlap in their biochemical and functional properties despite minor sequence variations. The SARS-CoV-2 E is a 75-amino acid transmembrane protein capable of acting as an ion channel when assembled in a pentameric fashion. Various studies have found that hexamethylene amiloride (HMA) can inhibit the ion channel activity of the E protein in bilayers and also inhibit viral replication in cultured cells. Here, we use the available structural data in conjunction with homology modelling to build a comprehensive model of the E protein to assess potential binding sites and molecular interactions of HMA derivatives. Furthermore, we employed an iterative cycle of molecular modelling, extensive docking simulations, molecular dynamics and leveraging steered molecular dynamics to better understand the pore characteristics and quantify the affinity of the bound ligands. Results from this work highlight the potential of acylguanidines as blockers of the E protein and guide the development of subsequent small molecule inhibitors. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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16 pages, 3878 KiB

Open AccessArticle

Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype

by Paulina Chałupnik, Alina Vialko, Darryl S. Pickering, Markus Hinkkanen, Stephanie Donbosco, Thor C. Møller, Anders A. Jensen, Birgitte Nielsen, Yasmin Bay, Anders S. Kristensen, Tommy N. Johansen, Kamil Łątka, Marek Bajda and Ewa Szymańska

Int. J. Mol. Sci. 2022, 23(15), 8797; https://doi.org/10.3390/ijms23158797 - 08 Aug 2022

Cited by 6 | Viewed by 2066

Abstract

Kainate receptors belong to the family of glutamate receptors ion channels, which are responsible for the majority of rapid excitatory synaptic transmission in the central nervous system. The therapeutic potential of kainate receptors is still poorly understood, which is also due to the lack of potent and subunit-selective pharmacological tools. In search of selective ligands for the GluK3 kainate receptor subtype, a series of quinoxaline-2,3-dione analogues was synthesized and pharmacologically characterized at selected recombinant ionotropic glutamate receptors. Among them, compound 28 was found to be a competitive GluK3 antagonist with submicromolar affinity and unprecedented high binding selectivity, showing a 400-fold preference for GluK3 over other homomeric receptors GluK1, GluK2, GluK5 and GluA2. Furthermore, in functional assays performed for selected metabotropic glutamate receptor subtypes, 28 did not show agonist or antagonist activity. The molecular determinants underlying the observed affinity profile of 28 were analyzed using molecular docking and molecular dynamics simulations performed for individual GluK1 and GluK3 ligand-binding domains. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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29 pages, 18144 KiB

Open AccessArticle

New Panx-1 Blockers: Synthesis, Biological Evaluation and Molecular Dynamic Studies

by Letizia Crocetti, Gabriella Guerrini, Maria Paola Giovannoni, Fabrizio Melani, Silvia Lamanna, Lorenzo Di Cesare Mannelli, Elena Lucarini, Carla Ghelardini, Junjie Wang and Gerhard Dahl

Int. J. Mol. Sci. 2022, 23(9), 4827; https://doi.org/10.3390/ijms23094827 - 27 Apr 2022

Cited by 6 | Viewed by 2251

Abstract

The channel protein Panx-1 is involved in some pathologies, such as epilepsy, ischemic stroke, cancer and Parkinson’s disease, as well as in neuropathic pain. These observations make Panx-1 an interesting biological target. We previously published some potent indole derivatives as Panx-1 blockers, and as continuation of the research in this field we report here the studies on additional chemical scaffolds, naphthalene and pyrazole, appropriately substituted with those functions that gave the best results as in our indole series (sulphonamide functions and one/two carboxylic groups) and in Panx-1 blockers reported in the literature (sulphonic acid). Compounds 4 and 13, the latter being an analogue of the drug Probenecid, are the most potent Panx-1 blockers obtained in this study, with I = 97% and I = 93.7% at 50 µM, respectively. Both compounds, tested in a mouse model of oxaliplatin-induced neuropathic pain, showed a similar anti-hypersensitivity profile and are able to significantly increase the mouse pain threshold 45 min after the injection of the doses of 1 nmol and 3 nmol. Finally, the molecular dynamic studies and the PCA analysis have made it possible to identify a discriminating factor able to separate active compounds from inactive ones. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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Review

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22 pages, 3435 KiB

Open AccessReview

Recent Advances in Computer-Aided Structure-Based Drug Design on Ion Channels

by Palina Pliushcheuskaya and Georg Künze

Int. J. Mol. Sci. 2023, 24(11), 9226; https://doi.org/10.3390/ijms24119226 - 25 May 2023

Cited by 2 | Viewed by 2460

Abstract

Ion channels play important roles in fundamental biological processes, such as electric signaling in cells, muscle contraction, hormone secretion, and regulation of the immune response. Targeting ion channels with drugs represents a treatment option for neurological and cardiovascular diseases, muscular degradation disorders, and pathologies related to disturbed pain sensation. While there are more than 300 different ion channels in the human organism, drugs have been developed only for some of them and currently available drugs lack selectivity. Computational approaches are an indispensable tool for drug discovery and can speed up, especially, the early development stages of lead identification and optimization. The number of molecular structures of ion channels has considerably increased over the last ten years, providing new opportunities for structure-based drug development. This review summarizes important knowledge about ion channel classification, structure, mechanisms, and pathology with the main focus on recent developments in the field of computer-aided, structure-based drug design on ion channels. We highlight studies that link structural data with modeling and chemoinformatic approaches for the identification and characterization of new molecules targeting ion channels. These approaches hold great potential to advance research on ion channel drugs in the future. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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22 pages, 11564 KiB

Open AccessReview

TRPV3 Ion Channel: From Gene to Pharmacology

by Aleksandr P. Kalinovskii, Lyubov L. Utkina, Yuliya V. Korolkova and Yaroslav A. Andreev

Int. J. Mol. Sci. 2023, 24(10), 8601; https://doi.org/10.3390/ijms24108601 - 11 May 2023

Cited by 3 | Viewed by 2078

Abstract

Transient receptor potential vanilloid subtype 3 (TRPV3) is an ion channel with a sensory function that is most abundantly expressed in keratinocytes and peripheral neurons. TRPV3 plays a role in Ca²⁺ homeostasis due to non-selective ionic conductivity and participates in signaling pathways associated with itch, dermatitis, hair growth, and skin regeneration. TRPV3 is a marker of pathological dysfunctions, and its expression is increased in conditions of injury and inflammation. There are also pathogenic mutant forms of the channel associated with genetic diseases. TRPV3 is considered as a potential therapeutic target of pain and itch, but there is a rather limited range of natural and synthetic ligands for this channel, most of which do not have high affinity and selectivity. In this review, we discuss the progress in the understanding of the evolution, structure, and pharmacology of TRPV3 in the context of the channel’s function in normal and pathological states. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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31 pages, 4219 KiB

Open AccessReview

Potassium Channels, Glucose Metabolism and Glycosylation in Cancer Cells

by Agata Wawrzkiewicz-Jałowiecka, Anna Lalik, Agnieszka Lukasiak, Monika Richter-Laskowska, Paulina Trybek, Maciej Ejfler, Maciej Opałka, Sonia Wardejn and Domenico V. Delfino

Int. J. Mol. Sci. 2023, 24(9), 7942; https://doi.org/10.3390/ijms24097942 - 27 Apr 2023

Cited by 3 | Viewed by 2949

Abstract

Potassium channels emerge as one of the crucial groups of proteins that shape the biology of cancer cells. Their involvement in processes like cell growth, migration, or electric signaling, seems obvious. However, the relationship between the function of

K^{+}

channels, glucose metabolism, [...] Read more.

K^{+}

channels, glucose metabolism, and cancer glycome appears much more intriguing. Among the typical hallmarks of cancer, one can mention the switch to aerobic glycolysis as the most favorable mechanism for glucose metabolism and glycome alterations. This review outlines the interconnections between the expression and activity of potassium channels, carbohydrate metabolism, and altered glycosylation in cancer cells, which have not been broadly discussed in the literature hitherto. Moreover, we propose the potential mediators for the described relations (e.g., enzymes, microRNAs) and the novel promising directions (e.g., glycans-orinented drugs) for further research. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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15 pages, 4471 KiB

Open AccessReview

Blockers of Skeletal Muscle Na_v1.4 Channels: From Therapy of Myotonic Syndrome to Molecular Determinants of Pharmacological Action and Back

by Michela De Bellis, Brigida Boccanegra, Alessandro Giovanni Cerchiara, Paola Imbrici and Annamaria De Luca

Int. J. Mol. Sci. 2023, 24(1), 857; https://doi.org/10.3390/ijms24010857 - 03 Jan 2023

Cited by 1 | Viewed by 1801

Abstract

The voltage-gated sodium channels represent an important target for drug discovery since a large number of physiological processes are regulated by these channels. In several excitability disorders, including epilepsy, cardiac arrhythmias, chronic pain, and non-dystrophic myotonia, blockers of voltage-gated sodium channels are clinically used. Myotonia is a skeletal muscle condition characterized by the over-excitability of the sarcolemma, resulting in delayed relaxation after contraction and muscle stiffness. The therapeutic management of this disorder relies on mexiletine and other sodium channel blockers, which are not selective for the Na_v1.4 skeletal muscle sodium channel isoform. Hence, the importance of deepening the knowledge of molecular requirements for developing more potent and use-dependent drugs acting on Na_v1.4. Here, we review the available treatment options for non-dystrophic myotonia and the structure–activity relationship studies performed in our laboratory with a focus on new compounds with potential antimyotonic activity. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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16 pages, 357 KiB

Open AccessReview

Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases

by Norbert Szentandrássy, Zsuzsanna É. Magyar, Judit Hevesi, Tamás Bányász, Péter P. Nánási and János Almássy

Int. J. Mol. Sci. 2022, 23(8), 4435; https://doi.org/10.3390/ijms23084435 - 18 Apr 2022

Cited by 12 | Viewed by 2772

Abstract

Cardiac diseases are the leading causes of death, with a growing number of cases worldwide, posing a challenge for both healthcare and research. Therefore, the most relevant aim of cardiac research is to unravel the molecular pathomechanisms and identify new therapeutic targets. Cardiac ryanodine receptor (RyR2), the Ca²⁺ release channel of the sarcoplasmic reticulum, is believed to be a good therapeutic target in a group of certain heart diseases, collectively called cardiac ryanopathies. Ryanopathies are associated with the impaired function of the RyR, leading to heart diseases such as congestive heart failure (CHF), catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and calcium release deficiency syndrome (CRDS). The aim of the current review is to provide a short insight into the pathological mechanisms of ryanopathies and discuss the pharmacological approaches targeting RyR2. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation)

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