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Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition

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: 15 December 2024 | Viewed by 5644

Special Issue Editors

Prof. Dr. Andrzej Kutner

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Guest Editor
Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, The Medical University of Warsaw, 1 Stefana Banacha, 02-097 Warsaw, Poland
Interests: medicinal chemistry; drug discovery; structure-activity relationships; design and synthesis of biologically active compounds; anticancer agents; crystal structure of biomolecules and ligand-receptor interactions, vitamin D analogs, pharmaceutical syntheses
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Geoffrey Brown

E-Mail Website
Guest Editor
School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Interests: the use of synthetic retinoids and vitamins D as drug substances; cancer and normal stem cells; anticancer therapies; blood cell development; abnormalities in cancer stem cells
Special Issues, Collections and Topics in MDPI journals
Dr. Enikö Kallay

E-Mail Website
Guest Editor
Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & Immunology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Interests: to understand and unveil biochemical and molecular mechanisms of the anti-tumourigenic effects of vitamin D and dietary calcium for colon cancer prevention; to examine the role of the calcium sensing receptor (CaSR) and of its natural and pharmacologic modulators in colon carcinogenesis and inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The last viral pandemic is now over. There is now a pressing need for the rapid development of effective and safe therapies for widespread diseases and, in particular for aggressive cancers whereby delays to diagnosis and treatment will lead to deaths that were otherwise manageable. In developing new therapies, areas of current interest are the efficacy of drug development-related strategies, entirely new therapeutic molecules, new drug delivery systems, and personalized and digital medicine. There is also the need to integrate various scientific disciplines and industrial activities that focus on these different aspects of drug research.

Volume 1.0 of the Special Issue “Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers” was very successful, with 21 papers. Volume 2.0, dedicated to the Interdisciplinary Conference on Drug Sciences, ACCORD 2022 was equally successful, with 25 papers. Both, Volumes 1.0 and 2.0 were also published as MDPI printed books (https://www.mdpi.com/books/book/5818-novel-strategies-in-the-development-of-new-therapies-drug-substances-and-drug-carriers and https://www.mdpi.com/books/book/7854-novel-strategies-in-the-development-of-new-therapies-drug-substances-and-drug-carriers-2-0).

Due to the continuing interest of authors, we are therefore reopening this topic as volume 3.0 in the International Journal of Molecular Sciences (ISSN 1422-0067, IF 5.6, JCR Category Q1). This third Special Issue aims to promote research in the fields that contribute to conceiving and developing a new drug substance and drug formulation. As with the previous Special Issues, this volume is not limited to any specific aspect of drug development. It aims to cover the entire process of drug development at the molecular level, to conform with the aims and scope of the Journal. Topics include the identification of the molecular target of a new drug, evaluating drug-protein interactions, the modeling, and optimization of functional activity, pre-formulation studies, pharmaceutical carrier development, and preclinical studies.

We would also like to draw your attention to the Interdisciplinary Conference on Drug Sciences, ACCORD 2024, to be held in Warsaw, Poland, 23–25 May 2024 (https://accord.wum.edu.pl/). All the participants of the ACCORD 2024 Conference will have the opportunity to publish a conference paper in this Special Issue. The manuscripts will undergo the regular peer-review process of the Journal.

All interested researchers are invited to submit original papers or review articles related to the topic of this Special Issue, guided by the “Aims and Scope”, “Instructions for Authors”, and the below keywords.

Prof. Dr. Andrzej Kutner
Prof. Dr. Geoffrey Brown
Dr. Enikö Kallay
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

  • drug design and discovery
  • antimicrobial drugs, antiviral drugs, antibiotics, cancer prevention and treatment
  • molecular modeling, molecular mechanisms, crystallography
  • preclinical studies, pharmacokinetics, pharmacodynamics, pharmacognosy
  • drug-protein interactions nuclear receptors, receptor agonists and antagonists, stem cells, activity profiling, vaccines, markers, and diagnostics
  • drug carriers, dosage form, anti-crystal engineering, nanoparticles, dissolution testing

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  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (5 papers)

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Research

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18 pages, 1886 KiB  
Article
Design and Synthesis of Potential Multi-Target Antidepressants: Exploration of 1-(4-(7-Azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione Derivatives with Affinity for the Serotonin Transporter
by Martyna Z. Wróbel, Andrzej Chodkowski, Agata Siwek, Grzegorz Satała, Andrzej J. Bojarski and Maciej Dawidowski
Int. J. Mol. Sci. 2024, 25(20), 11276; https://doi.org/10.3390/ijms252011276 - 20 Oct 2024
Viewed by 697
Abstract
We describe the design, synthesis and structure–activity relationship of a novel series of 1-(4-(7-azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with combined effects on the serotonin (5-HT1A) and dopamine (D2) receptors and the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters as [...] Read more.
We describe the design, synthesis and structure–activity relationship of a novel series of 1-(4-(7-azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with combined effects on the serotonin (5-HT1A) and dopamine (D2) receptors and the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters as multi-target directed ligands for the treatment of depression. All of the tested compounds demonstrated good affinity for the serotonin transporter (SERT). Among them, compounds 11 and 4 emerged as the lead candidates because of their promising pharmacological profile based on in vitro studies. Compound 11 displayed a high affinity for the 5-HT1A (Ki = 128.0 nM) and D2 (Ki = 51.0 nM) receptors, and the SERT (Ki = 9.2 nM) and DAT (Ki = 288.0 nM) transporters, whereas compound 4 exhibited the most desirable binding profile to SERT/NET/DAT among the series: Ki = 47.0 nM/167.0 nM/43% inhibition at 1 µM. These results suggest that compounds 4 and 11 represent templates for the future development of multi-target antidepressant drugs. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)
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17 pages, 1746 KiB  
Article
Assessment of Dried Serum Spots (DSS) and Volumetric-Absorptive Microsampling (VAMS) Techniques in Therapeutic Drug Monitoring of (Val)Ganciclovir—Comparative Study in Analytical and Clinical Practice
by Arkadiusz Kocur, Agnieszka Czajkowska, Mateusz Moczulski, Bartłomiej Kot, Jacek Rubik and Tomasz Pawiński
Int. J. Mol. Sci. 2024, 25(16), 8760; https://doi.org/10.3390/ijms25168760 - 12 Aug 2024
Viewed by 817
Abstract
Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are antiviral medications primarily used to treat infections caused by cytomegalovirus (CMV), particularly in immunocompromised individuals such as solid organ transplant (SOT) recipients. Therapy with GCV is associated with significant side effects, including bone marrow suppression. [...] Read more.
Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are antiviral medications primarily used to treat infections caused by cytomegalovirus (CMV), particularly in immunocompromised individuals such as solid organ transplant (SOT) recipients. Therapy with GCV is associated with significant side effects, including bone marrow suppression. Therefore, therapeutic drug monitoring (TDM) is mandatory for an appropriate balance between subtherapeutic and toxic drug levels. This study aimed to develop and validate three novel methods based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for GCV determination in serum (reference methodology), dried serum spots (DSS), and VAMS-Mitra™ devices. The methods were optimized and validated in the 0.1–25 mg/L calibration range. The obtained results fulfilled the EMA acceptance criteria for bioanalytical method validation. Assessment of DSS and VAMS techniques extended GCV stability to serum for up to a minimum of 49 days (at room temperature, with desiccant). Developed methods were effectively evaluated using 80 clinical serum samples from pediatric renal transplant recipients. Obtained samples were used for DSS, and dried serum VAMS samples were manually generated in the laboratory. The results of GCV determination using serum-, DSS- and VAMS-LC-MS/MS methods were compared using regression analysis and bias evaluation. The conducted statistical analysis confirmed the interchangeability between developed assays. The DSS and VAMS samples are more accessible and stable during storage, transport and shipment than classic serum samples. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)
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Review

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21 pages, 1224 KiB  
Review
Towards Targeting Endothelial Rap1B to Overcome Vascular Immunosuppression in Cancer
by Behshid Ghadrdoost Nakhchi, Ramoji Kosuru and Magdalena Chrzanowska
Int. J. Mol. Sci. 2024, 25(18), 9853; https://doi.org/10.3390/ijms25189853 - 12 Sep 2024
Viewed by 1057
Abstract
The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular [...] Read more.
The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression—a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8+ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A’s immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies’ efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)
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21 pages, 4223 KiB  
Review
Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ
by Katarzyna Powała, Teresa Żołek, Geoffrey Brown and Andrzej Kutner
Int. J. Mol. Sci. 2024, 25(12), 6568; https://doi.org/10.3390/ijms25126568 - 14 Jun 2024
Viewed by 1371
Abstract
All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, [...] Read more.
All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)
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Other

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8 pages, 581 KiB  
Case Report
Pseudohyperaldosteronism Due to Licorice: A Practice-Based Learning from a Case Series
by Chiara Sabbadin, Andrea Graziani, Alessandro Bavaresco, Pierluigi Mazzeo, Irene Tizianel, Filippo Ceccato, Decio Armanini and Mattia Barbot
Int. J. Mol. Sci. 2024, 25(13), 7454; https://doi.org/10.3390/ijms25137454 - 7 Jul 2024
Cited by 1 | Viewed by 1042
Abstract
Pseudohyperaldosteronism (PHA) is characterized by hypertension, hypokalemia, and a decrease in plasma renin and aldosterone levels. It can be caused by several causes, but the most frequent is due to excess intake of licorice. The effect is mediated by the active metabolite of [...] Read more.
Pseudohyperaldosteronism (PHA) is characterized by hypertension, hypokalemia, and a decrease in plasma renin and aldosterone levels. It can be caused by several causes, but the most frequent is due to excess intake of licorice. The effect is mediated by the active metabolite of licorice, glycyrrhetinic acid (GA), which acts by blocking the 11-hydroxysteroid dehydrogenase type 2 and binding to the mineralocorticoid receptor (MR) as an agonist. The management of licorice-induced PHA depends on several individual factors, such as age, gender, comorbidities, duration and amount of licorice intake, and metabolism. The clinical picture usually reverts upon licorice withdrawal, but sometimes mineralocorticoid-like effects can be critical and persist for several weeks, requiring treatment with MR blockers and potassium supplements. Through this case series of licorice-induced PHA, we aim to increase awareness about exogenous PHA, and the possible risk associated with excess intake of licorice. An accurate history is mandatory in patients with hypertension and hypokalemia to avoid unnecessary testing. GA is a component of several products, such as candies, breath fresheners, beverages, tobacco, cosmetics, and laxatives. In recent years, the mechanisms of action of licorice and its active compounds have been better elucidated, suggesting its benefits in several clinical settings. Nevertheless, licorice should still be consumed with caution, considering that licorice-induced PHA is still an underestimated condition, and its intake should be avoided in patients with increased risk of licorice toxicity due to concomitant comorbidities or interfering drugs. Full article
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 3rd Edition)
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