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State-of-the-Art Molecular Pharmacology in Spain

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 17610

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Prof. Dr. Asia Fernandez Carvajal

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Collection Editor

Institute of Molecular and Cell Biology, Miguel Hernandez University, Elche, Spain
Interests: high-throughput screening; discovery and development of anti-nociceptive drugs; structure–function studies on TRP ion channels; translational research in the field of sensory neurobiology; role of thermoTRP channels in the pathophysiology of migraine
Special Issues, Collections and Topics in MDPI journals

Dr. Gerard Pujadas

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Collection Editor

Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
Interests: drug discovery; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pharmacology is a discipline which deals with the interaction of natural, semisynthetic or fully (bio)synthetic therapeutic agents at the cellular and organismal levels. These therapeutic agents can range from small molecules through to macromolecules such as proteins and antibodies. Thus, this field is positioned at the interface of pharmacy/chemistry and physiology/pathophysiology in their broadest sense. It operates at various organizational levels, such as the molecular, subcellular, cellular, organ and systemic platforms. Molecular pharmacology investigates the molecular mode of action of therapeutic agents using cellular, genetic and molecular biology approaches, and is among the most rapidly developing fields of pharmacology.

Original research and review articles on molecular pharmacology are invited to submit to this topical collection. The "Molecular Pharmacology" section aims to publish the latest developments in cellular and molecular pharmacology with a major emphasis on the mechanism of action of novel drugs, innovative pharmacological technologies, cell signaling, transduction pathway analysis, genomics, proteomics and metabonomics applications in drug action. An additional focus will be the way in which normal biological function is illuminated by knowledge of the action of drugs at the cellular and molecular level.

A large number of research teams in Spain from different institutions and universities are currently working together and devoting considerable efforts to develop and study molecular pharmacology. This topical collection is committed to providing an overview of the macromolecular sciences and technologies in Spain.

Prof. Dr. Asia Fernandez Carvajal
Dr. Gerard Pujadas
Collection 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

signal transduction
receptor
animal models
preclinical
pharmacodynamics
pharmacokinetics
drug development
drug metabolism
drug delivery
CADD
virtual screening

Published Papers (9 papers)

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Research

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19 pages, 12554 KiB

Open AccessArticle

Enhanced NSAIDs Solubility in Drug–Drug Formulations with Ciprofloxacin

by Francisco Javier Acebedo-Martínez, Alicia Domínguez-Martín, Carolina Alarcón-Payer, Alejandro Sevillano-Páez, Cristóbal Verdugo-Escamilla, Josefa María González-Pérez, Fernando Martínez-Checa and Duane Choquesillo-Lazarte

Int. J. Mol. Sci. 2023, 24(4), 3305; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043305 - 07 Feb 2023

Cited by 2 | Viewed by 1523

Abstract

Drug–drug salts are a kind of pharmaceutical multicomponent solid in which the two co-existing components are active pharmaceutical ingredients (APIs) in their ionized forms. This novel approach has attracted great interest in the pharmaceutical industry since it not only allows concomitant formulations but also has proved potential to improve the pharmacokinetics of the involved APIs. This is especially interesting for those APIs that have relevant dose-dependent secondary effects, such as non-steroidal anti-inflammatory drugs (NSAIDs). In this work, six multidrug salts involving six different NSAIDs and the antibiotic ciprofloxacin are reported. The novel solids were synthesized using mechanochemical methods and comprehensively characterized in the solid state. Moreover, solubility and stability studies, as well as bacterial inhibition assays, were performed. Our results suggest that our drug–drug formulations enhanced the solubility of NSAIDs without affecting the antibiotic efficacy. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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17 pages, 3218 KiB

Open AccessArticle

Miltefosine and Nifuratel Combination: A Promising Therapy for the Treatment of Leishmania donovani Visceral Leishmaniasis

by Estela Melcon-Fernandez, Giulio Galli, Carlos García-Estrada, Rafael Balaña-Fouce, Rosa M. Reguera and Yolanda Pérez-Pertejo

Int. J. Mol. Sci. 2023, 24(2), 1635; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021635 - 13 Jan 2023

Cited by 5 | Viewed by 2033

Abstract

Visceral leishmaniasis is a neglected vector-borne tropical disease caused by Leishmania donovani and Leishmania infantum that is endemic not only in East African countries, but also in Asia, regions of South America and the Mediterranean Basin. For the pharmacological control of this disease, there is a limited number of old and, in general, poorly adherent drugs, with a multitude of adverse effects and low oral bioavailability, which favor the emergence of resistant pathogens. Pentavalent antimonials are the first-line drugs, but due to their misuse, resistant Leishmania strains have emerged worldwide. Although these drugs have saved many lives, it is recommended to reduce their use as much as possible and replace them with novel and more friendly drugs. From a commercial collection of anti-infective drugs, we have recently identified nifuratel—a nitrofurantoin used against vaginal infections—as a promising repurposing drug against a mouse model of visceral leishmaniasis. In the present work, we have tested combinations of miltefosine—the only oral drug currently used against leishmaniasis—with nifuratel in different proportions, both in axenic amastigotes from bone marrow and in intracellular amastigotes from infected Balb/c mouse spleen macrophages, finding a potent synergy in both cases. In vivo evaluation of oral miltefosine/nifuratel combinations using a bioimaging platform has revealed the potential of these combinations for the treatment of this disease. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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12 pages, 2861 KiB

Open AccessArticle

Screening System of Cannabis sativa Extracts Based on Their Mitochondrial Safety Profile Using Cytochrome c Oxidase Activity as a Biomarker

by Ekaterina Noskova, Roberto Fernández, Javier García, Eneko Ochoa, Celtia Domínguez-Fernández, Albert Adell, Antonio Laso, Maria Fe Andrés, Azucena González-Coloma, Egoitz Astigarraga and Gabriel Barreda-Gómez

Int. J. Mol. Sci. 2023, 24(2), 1315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021315 - 10 Jan 2023

Cited by 3 | Viewed by 1877

Abstract

The development of Cannabis sativa strains with high cannabidiol (CBD) and low tetrahydrocannabinol (THC) content is a growing field of research, both for medical and recreational use. However, the mechanisms behind clinical actions of cannabinoids are still under investigation, although there is growing evidence that mitochondria play an important role in many of them. Numerous studies have described that cannabinoids modulate mitochondrial activity both through activation of mitochondrial cannabinoid receptors and through direct action on other proteins such as mitochondrial complexes involved in cellular respiration. Thus, the aim of this study was to determine the actions of a panel of extracts, isolated from high-CBD varieties of Cannabis sativa, on the activity of the mitochondrial electron transport chain complex IV, cytochrome c oxidase (CCO), in order to select those with a safer profile. After demonstrating that Cannabis sativa strains could be identified by cannabinoids content, concentration–response curves were performed with a collection of extracts from strains with high-CBD and low-THC content using bovine CCO. The CCO rate was clearly modified by specific extracts of Cannabis sativa plants compared to others. Half maximal inhibitory concentrations (IC50) of extracts and the inhibitory effects evoked at 1 × 10⁻⁴ g/mL displayed a significant correlation with the THC. Therefore, the screening of extracts based on CCO activity provides a powerful and rapid methodology to identify those plants with higher mitochondrial toxicity or even mito-protective actions. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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18 pages, 4612 KiB

Open AccessArticle

1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs

by Oriol Bosch-Sanz, Yvette Rabadà, Xevi Biarnés, Javier Pedreño, Luis Caveda, Mercedes Balcells, Jordi Martorell and David Sánchez-García

Int. J. Mol. Sci. 2022, 23(23), 14942; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314942 - 29 Nov 2022

Cited by 1 | Viewed by 1989

Abstract

Fibrinolysis is a natural process that ensures blood fluidity through the removal of fibrin deposits. However, excessive fibrinolytic activity can lead to complications in different circumstances, such as general surgery or severe trauma. The current antifibrinolytic drugs in the market, aminocaproic acid (EACA) and tranexamic acid (TXA), require high doses repetitively to maintain their therapeutic effect. These high doses are related to a number of side effects such as headaches, nasal symptoms, or gastrointestinal discomfort and severely limit their use in patients with renal impairment. Therefore, the discovery of novel antifibrinolytics with a higher specificity and lower dosage could vastly improve the applicability of these drugs. Herein, we synthesized a total of ten compounds consisting of a combination of three key moieties: an oxadiazolone, a triazole, and a terminal amine. The IC₅₀ of each compound was calculated in our clot lysis assays, and the best candidate (1) provided approximately a 2.5-fold improvement over the current gold standard, TXA. Molecular docking and molecular dynamics were used to perform a structure–activity relationship (SAR) analysis with the lysine binding site in the Kringle 1 domain of plasminogen. This analysis revealed that 1,2,3-triazole was crucial for the activity, enhancing the binding affinity through pi–pi stacking and polar interactions with Tyr72. The results presented in this work open the door to further investigate this new family as potential antifibrinolytic drugs. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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18 pages, 2412 KiB

Open AccessArticle

The BRCT Domain from the Homologue of the Oncogene PES1 in Leishmania major (LmjPES) Promotes Malignancy and Drug Resistance in Mammalian Cells

by Esther Larrea, Celia Fernández-Rubio, José Peña-Guerrero, Elizabeth Guruceaga and Paul A. Nguewa

Int. J. Mol. Sci. 2022, 23(21), 13203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113203 - 30 Oct 2022

Cited by 2 | Viewed by 1394

Abstract

Around 15% of cancer cases are attributable to infectious agents. Epidemiological studies suggest that an association between leishmaniasis and cancer does exist. Recently, the homologue of PES1 in Leishmania major (LmjPES) was described to be involved in parasite infectivity. Mammalian PES1 protein has been implicated in cellular processes like cell cycle regulation. Its BRCT domain has been identified as a key factor in DNA damage-responsive checkpoints. This work aimed to elucidate the hypothetical oncogenic implication of BRCT domain from LmjPES in host cells. We generated a lentivirus carrying this BRCT domain sequence (lentiBRCT) and a lentivirus expressing the luciferase protein (lentiLuc), as control. Then, HEK293T and NIH/3T3 mammalian cells were infected with these lentiviruses. We observed that the expression of BRCT domain from LmjPES conferred to mammal cells in vitro a greater replication rate and higher survival. In in vivo experiments, we observed faster tumor growth in mice inoculated with lentiBRCT respect to lentiLuc HEK293T infected cells. Moreover, the lentiBRCT infected cells were less sensitive to the genotoxic drugs. Accordingly, gene expression profiling analysis revealed that BRCT domain from LmjPES protein altered the expression of proliferation- (DTX3L, CPA4, BHLHE41, BMP2, DHRS2, S100A1 and PARP9), survival- (BMP2 and CARD9) and chemoresistance-related genes (DPYD, Dok3, DTX3L, PARP9 and DHRS2). Altogether, our results reinforced the idea that in eukaryotes, horizontal gene transfer might be also achieved by parasitism like Leishmania infection driving therefore to some crucial biological changes such as proliferation and drug resistance. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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18 pages, 3998 KiB

Open AccessArticle

Topical Administration of a Marine Oil Rich in Pro-Resolving Lipid Mediators Accelerates Wound Healing in Diabetic db/db Mice through Angiogenesis and Macrophage Polarization

by Imelda Ontoria-Oviedo, Elena Amaro-Prellezo, Delia Castellano, Elena Venegas-Venegas, Fernando González-Santos, Amparo Ruiz-Saurí, Beatriz Pelacho, Felipe Prósper, María Dolores Pérez del Caz and Pilar Sepúlveda

Int. J. Mol. Sci. 2022, 23(17), 9918; https://doi.org/10.3390/ijms23179918 - 31 Aug 2022

Cited by 8 | Viewed by 2176

Abstract

Impaired wound healing in patients with type 2 diabetes (DM2) is characterized by chronic inflammation, which delays wound closure. Specialized pro-resolving lipid mediators (SPMs) are bioactive molecules produced from essential polyunsaturated fatty acids (PUFAs), principally omega-3 docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). SPMs are potent regulators of inflammation and have been used to suppress chronic inflammation in peripheral artery disease, non-alcoholic fatty liver disease, and central nervous system syndromes. LIPINOVA^® is a commercially available safe-grade nutritional supplement made from a fractionated marine lipid concentrate derived from anchovy and sardine oil that is rich in SPMs and EPA, as well as DHA precursors. Here, we assessed the effect of LIPINOVA^® in wound dressing applications. LIPINOVA^® showed biocompatibility with keratinocytes and fibroblasts, reduced the abundance of pro-inflammatory macrophages (Mφ1), and promoted in vitro wound closure. Daily application of the marine oil to open wounds made by punch biopsy in db/db mice promoted wound closure by accelerating the resolution of inflammation, inducing neoangiogenesis and Mφ1/Mφ2 macrophage polarization. In conclusion, LIPINOVA^® displays pro-resolutive properties and could be exploited as a therapeutic agent for the treatment of diabetic ulcers. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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Review

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27 pages, 8912 KiB

Open AccessReview

Biological Use of Nanostructured Silica-Based Materials Functionalized with Metallodrugs: The Spanish Perspective

by Diana Díaz-García, Sanjiv Prashar and Santiago Gómez-Ruiz

Int. J. Mol. Sci. 2023, 24(3), 2332; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032332 - 25 Jan 2023

Cited by 5 | Viewed by 1770

Abstract

Since the pioneering work of Vallet-Regí’s group on the design and synthesis of mesoporous silica-based materials with therapeutic applications, during the last 15 years, the potential use of mesoporous silica nanostructured materials as drug delivery vehicles has been extensively explored. The versatility of these materials allows the design of a wide variety of platforms that can incorporate numerous agents of interest (fluorophores, proteins, drugs, etc.) in a single scaffold. However, the use of these systems loaded with metallodrugs as cytotoxic agents against different diseases and with distinct therapeutic targets has been studied to a much lesser extent. This review will focus on the work carried out in this field, highlighting both the pioneering and recent contributions of Spanish groups that have synthesized a wide variety of systems based on titanium, tin, ruthenium, copper and silver complexes supported onto nanostructured silica. In addition, this article will also discuss the importance of the structural features of the systems for evaluating and modulating their therapeutic properties. Finally, the most interesting results obtained in the study of the potential therapeutic application of these metallodrug-functionalized silica-based materials against cancer and bacteria will be described, paying special attention to preclinical trials in vivo. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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12 pages, 1564 KiB

Open AccessReview

Recent PELE Developments and Applications in Drug Discovery Campaigns

by Ignasi Puch-Giner, Alexis Molina, Martí Municoy, Carles Pérez and Victor Guallar

Int. J. Mol. Sci. 2022, 23(24), 16090; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232416090 - 17 Dec 2022

Viewed by 1910

Abstract

Computer simulation techniques are gaining a central role in molecular pharmacology. Due to several factors, including the significant improvements of traditional molecular modelling, the irruption of machine learning methods, the massive data generation, or the unlimited computational resources through cloud computing, the future of pharmacology seems to go hand in hand with in silico predictions. In this review, we summarize our recent efforts in such a direction, centered on the unconventional Monte Carlo PELE software and on its coupling with machine learning techniques. We also provide new data on combining two recent new techniques, aquaPELE capable of exhaustive water sampling and fragPELE, for fragment growing. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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Other

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11 pages, 1590 KiB

Open AccessBrief Report

Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection

by Ifeanyi Jude Ezeonwumelu, Edurne Garcia-Vidal, Eva Riveira-Muñoz, Eudald Felip, Lucía Gutiérrez-Chamorro, Ignasi Calba, Marta Massanella, Guillem Sirera, Bonaventura Clotet, Ester Ballana and Roger Badia

Int. J. Mol. Sci. 2022, 23(23), 15000; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315000 - 30 Nov 2022

Viewed by 1274

Abstract

HIV latent infection may be associated with disrupted viral RNA sensing, interferon (IFN) signaling, and/or IFN stimulating genes (ISG) activation. Here, we evaluated the use of compounds selectively targeting at the inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex subunits and related kinases (TBK1) as a novel pathway to reverse HIV-1 latency in latently infected non-clonal lymphoid and myeloid cell in vitro models. IKK inhibitors (IKKis) triggered up to a 1.8-fold increase in HIV reactivation in both, myeloid and lymphoid cell models. The best-in-class IKKis, targeting TBK-1 (MRT67307) and IKKβ (TCPA-1) respectively, were also able to significantly induce viral reactivation in CD4+ T cells from people living with HIV (PLWH) ex vivo. More importantly, although none of the compounds tested showed antiviral activity, the combination of the distinct IKKis with ART did not affect the latency reactivation nor blockade of HIV infection by ART. Finally, as expected, IKKis did not upregulate cell activation markers in primary lymphocytes and innate immune signaling was blocked, resulting in downregulation of inflammatory cytokines. Overall, our results support a dual role of IKKis as immune modulators being able to tackle the HIV latent reservoir in lymphoid and myeloid cellular models and putatively control the hyperinflammatory responses in chronic HIV-1 infection. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Pharmacology in Spain)

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