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Biomedicines
Special Issues
State-of-the-Art Drug Discovery and Development in Spain
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State-of-the-Art Drug Discovery and Development in Spain

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 19395

Special Issue Editors

Prof. Dr. Silvia Ortega-Gutierrez

E-Mail Website
Guest Editor
Organic Chemistry Department, School of Chemistry Universidad Complutense de Madrid, 28040 Madrid, Spain
Interests: medicinal chemistry; chemical biology; chemical probes; GPCRs; endogenous cannabinoid system; monoacylglycerol lipase (MAGL); isoprenylcarboxylmethyl transferase (ICMT); lysophosphatidic acid receptors (LPARs); progeria
Prof. Dr. María L. López-Rodríguez

E-Mail Website
Guest Editor
Department Química Orgánica, Facultad de Ciencias Químicas, UCM, Avda. Complutense s/n, 28040 Madrid, Spain
Interests: medicinal chemistry; biological chemistry; G-protein coupled receptors (GPCRs); allosteric modulation of GPCRs; lysophosphatidic acid receptors (LPA); FtsZ bacterial division protein; NPM1 protein; antibody-drug conjugates; senescence

Special Issue Information

Dear Colleagues,

This Special Issue focuses on State-of-the-Art Drug Discovery and Development in Spain, in its broadest sense. Drug discovery and development is a rapidly changing and very dynamic arena, and Spain is one of the European hubs driving new knowledge both in academia and industry. In spite of the continuous advances, constant health challenges appear, as we have witnessed these last years with the global COVID-19 pandemia or with different pathologies that represent important threats to our daily well-being, in the current moment or in the near future, such as cancer, viral and bacterial infections, cardiovascular and neurodegenerative diseases, and ageing.

Therefore, we invite all authors actively contributing to the Spanish drug discovery and development arena to participate in this Special Issue. Original research articles and reviews dealing with new strategies with the potential to provide novel treatments in the short term will be welcomed, as will manuscripts dealing with the hottest topics in drug discovery and cutting-edge methodological advances, including emerging industry trends and strategies in relationship with recent drug approvals.

Prof. Dr. Silvia Ortega-Gutierrez
Prof. Dr. María L. López-Rodríguez
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. Biomedicines 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 2600 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

  • medicinal chemistry
  • chemical biology
  • computational chemistry
  • drug design
  • antibiotics
  • antivirals
  • cancer
  • neurodegenerative diseases
  • ageing
  • cardiovascular disease
  • small molecules
  • biologicals
  • peptidomimetics
  • enzyme inhibitors
  • targeted therapy
  • bioimaging
  • biomarkers

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Published Papers (6 papers)

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Research

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23 pages, 5211 KiB  
Article
Small Molecules as Toll-like Receptor 4 Modulators Drug and In-House Computational Repurposing
by Lucía Pérez-Regidor, Joan Guzmán-Caldentey, Nils Oberhauser, Carmen Punzón, Balázs Balogh, José R. Pedro, Eva Falomir, Alessandra Nurisso, Péter Mátyus, J. Carlos Menéndez, Belén de Andrés, Manuel Fresno and Sonsoles Martín-Santamaría
Biomedicines 2022, 10(9), 2326; https://doi.org/10.3390/biomedicines10092326 - 19 Sep 2022
Cited by 6 | Viewed by 3108
Abstract
The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a “computer-aided drug repurposing” approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 [...] Read more.
The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a “computer-aided drug repurposing” approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and in-house academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity. Our computational protocol showed to be a robust approach for the identification of hits with drug-like scaffolds as possible inhibitors of the TLR4 innate immune pathways. Our collaborative work broadens the chemical diversity for inspiration of new classes of TLR4 modulators. Full article
(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Spain)
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16 pages, 2415 KiB  
Article
Analysis of Mitochondrial Function in Cell Membranes as Indicator of Tissue Vulnerability to Drugs in Humans
by Ane Elexpe, Laura Sánchez-Sánchez, Tarson Tolentino-Cortez, Egoitz Astigarraga, María Torrecilla and Gabriel Barreda-Gómez
Biomedicines 2022, 10(5), 980; https://doi.org/10.3390/biomedicines10050980 - 23 Apr 2022
Cited by 2 | Viewed by 2006
Abstract
Drug side effects are one of the main reasons for treatment withdrawal during clinical trials. Reactive oxygen species formation is involved in many of the drug side effects, mainly by interacting with the components of the cellular respiration. Thus, the early detection of [...] Read more.
Drug side effects are one of the main reasons for treatment withdrawal during clinical trials. Reactive oxygen species formation is involved in many of the drug side effects, mainly by interacting with the components of the cellular respiration. Thus, the early detection of these effects in the drug discovery process is a key aspect for the optimization of pharmacological research. To this end, the superoxide formation of a series of drugs and compounds with antidepressant, antipsychotic, anticholinergic, narcotic, and analgesic properties was evaluated in isolated bovine heart membranes and on cell membrane microarrays from a collection of human tissues, together with specific inhibitors of the mitochondrial electron transport chain. Fluphenazine and PB28 promoted similar effects to those of rotenone, but with lower potency, indicating a direct action on mitochondrial complex I. Moreover, nefazodone, a drug withdrawn from the market due to its mitochondrial hepatotoxic effects, evoked the highest superoxide formation in human liver cell membranes, suggesting the potential of this technology to anticipate adverse effects in preclinical phases. Full article
(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Spain)
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14 pages, 2404 KiB  
Article
In Vitro Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside
by Estefanía Burgos-Morón, Nuria Pastor, Manuel Luis Orta, Julio José Jiménez-Alonso, Carlos Palo-Nieto, Margarita Vega-Holm, José Manuel Vega-Pérez, Fernando Iglesias-Guerra, Santiago Mateos, Miguel López-Lázaro and José Manuel Calderón-Montaño
Biomedicines 2022, 10(1), 41; https://doi.org/10.3390/biomedicines10010041 - 25 Dec 2021
Cited by 2 | Viewed by 2953
Abstract
We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore the possible mechanisms involved in the cytotoxicity of this aziridine and evaluate [...] Read more.
We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore the possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (comet assay). Cells deficient in the nucleotide excision repair (NER) pathway were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. Combinations of AzGalp with oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also showed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp. Full article
(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Spain)
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Review

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27 pages, 2585 KiB  
Review
New Trends in Aging Drug Discovery
by Bellinda Benhamú, Mar Martín-Fontecha, Henar Vázquez-Villa, María L. López-Rodríguez and Silvia Ortega-Gutiérrez
Biomedicines 2022, 10(8), 2006; https://doi.org/10.3390/biomedicines10082006 - 18 Aug 2022
Cited by 4 | Viewed by 4520
Abstract
Aging is considered the main risk factor for many chronic diseases that frequently appear at advanced ages. However, the inevitability of this process is being questioned by recent research that suggests that senescent cells have specific features that differentiate them from younger cells [...] Read more.
Aging is considered the main risk factor for many chronic diseases that frequently appear at advanced ages. However, the inevitability of this process is being questioned by recent research that suggests that senescent cells have specific features that differentiate them from younger cells and that removal of these cells ameliorates senescent phenotype and associated diseases. This opens the door to the design of tailored therapeutic interventions aimed at reducing and delaying the impact of senescence in life, that is, extending healthspan and treating aging as another chronic disease. Although these ideas are still far from reaching the bedside, it is conceivable that they will revolutionize the way we understand aging in the next decades. In this review, we analyze the main and well-validated cellular pathways and targets related to senescence as well as their implication in aging-associated diseases. In addition, the most relevant small molecules with senotherapeutic potential, with a special emphasis on their mechanism of action, ongoing clinical trials, and potential limitations, are discussed. Finally, a brief overview of alternative strategies that go beyond the small molecule field, together with our perspectives for the future of the field, is provided. Full article
(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Spain)
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18 pages, 3754 KiB  
Review
The Search for Antibacterial Inhibitors Targeting Cell Division Protein FtsZ at Its Nucleotide and Allosteric Binding Sites
by José M. Andreu, Sonia Huecas, Lidia Araújo-Bazán, Henar Vázquez-Villa and Mar Martín-Fontecha
Biomedicines 2022, 10(8), 1825; https://doi.org/10.3390/biomedicines10081825 - 28 Jul 2022
Cited by 16 | Viewed by 2953
Abstract
The global spread of bacterial antimicrobial resistance is associated to millions of deaths from bacterial infections per year, many of which were previously treatable. This, combined with slow antibiotic deployment, has created an urgent need for developing new antibiotics. A still clinically unexploited [...] Read more.
The global spread of bacterial antimicrobial resistance is associated to millions of deaths from bacterial infections per year, many of which were previously treatable. This, combined with slow antibiotic deployment, has created an urgent need for developing new antibiotics. A still clinically unexploited mode of action consists in suppressing bacterial cell division. FtsZ, an assembling GTPase, is the key protein organizing division in most bacteria and an attractive target for antibiotic discovery. Nevertheless, developing effective antibacterial inhibitors targeting FtsZ has proven challenging. Here we review our decade-long multidisciplinary research on small molecule inhibitors of bacterial division, in the context of global efforts to discover FtsZ-targeting antibiotics. We focus on methods to characterize synthetic inhibitors that either replace bound GTP from the FtsZ nucleotide binding pocket conserved across diverse bacteria or selectively bind into the allosteric site at the interdomain cleft of FtsZ from Bacillus subtilis and the pathogen Staphylococcus aureus. These approaches include phenotype screening combined with fluorescence polarization screens for ligands binding into each site, followed by detailed cytological profiling, and biochemical and structural studies. The results are analyzed to design an optimized workflow to identify effective FtsZ inhibitors, and new approaches for the discovery of FtsZ-targeting antibiotics are discussed. Full article
(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Spain)
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18 pages, 6031 KiB  
Review
Heterocycle-Based Multicomponent Reactions in Drug Discovery: From Hit Finding to Rational Design
by Pau Nadal Rodríguez, Ouldouz Ghashghaei, Andrea Bagán, Carmen Escolano and Rodolfo Lavilla
Biomedicines 2022, 10(7), 1488; https://doi.org/10.3390/biomedicines10071488 - 23 Jun 2022
Cited by 11 | Viewed by 2869
Abstract
In the context of the structural complexity necessary for a molecule to selectively display a therapeutical action and the requirements for suitable pharmacokinetics, a robust synthetic approach is essential. Typically, thousands of relatively similar compounds should be prepared along the drug discovery process. [...] Read more.
In the context of the structural complexity necessary for a molecule to selectively display a therapeutical action and the requirements for suitable pharmacokinetics, a robust synthetic approach is essential. Typically, thousands of relatively similar compounds should be prepared along the drug discovery process. In this respect, heterocycle-based multicomponent reactions offer advantages over traditional stepwise sequences in terms of synthetic economy, as well as the fast access to chemsets to study the structure activity relationships, the fine tuning of properties, and the preparation of larger amounts for preclinical phases. In this account, we briefly summarize the scientific methodology backing the research line followed by the group. We comment on the main results, clustered according to the targets and, finally, in the conclusion section, we offer a general appraisal of the situation and some perspectives regarding future directions in academic and private research. Full article
(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Spain)
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