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Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 31 May 2026 | Viewed by 4711

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Dr. Vanessa Mateus

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1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
2. H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
Interests: pharmacology; pharmacotherapy; non-clinical studies in vivo; animal models of disease; inflammation; inflammatory bowel disease

Special Issue Information

Dear Colleagues,

The Special Issue "Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research" aims to explore innovative advances in pharmacology, focusing on the molecular underpinnings that drive drug efficacy and safety in nonclinical models. As the complexity of disease biology becomes increasingly evident, the development of targeted pharmacological interventions requires an in-depth understanding of their molecular and cellular pathways. This Special Issue seeks to gather original research and systematic reviews on novel drug targets, signalling cascades, receptor–drug interactions, gene expression modulation, and molecular biomarkers predictive of therapeutic response.

Particular emphasis will be placed on studies employing in vivo models to uncover mechanistic insights into drug action. Contributions may also include innovative drug delivery approaches, pharmacological structure–activity relationships, and pharmacogenomic strategies. By bridging molecular mechanisms with pharmacological innovation, this Special Issue aims to provide a comprehensive overview of how molecular-level research can be integrated with preclinical development to guide the rational design of next-generation therapeutics, enhancing their translational potential.

Researchers from pharmacology, molecular biology, and related disciplines are invited to contribute to this Special Issue, which aims to promote interdisciplinary dialogue and accelerate the bench-to-bedside transition of novel pharmacological strategies.

Dr. Vanessa Mateus
Guest Editor

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Keywords

molecular pharmacology
drug targets
signal transduction pathways
nonclinical models
receptor-ligand interactions
pharmacogenomics
preclinical drug development
gene expression modulation
mechanism of action
translational pharmacology

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Published Papers (6 papers)

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Research

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14 pages, 2175 KB

Open AccessArticle

Salbutamol and Formoterol Attenuate Okadaic Acid-Induced Cytotoxicity in Undifferentiated PC-12 Cells: Evidence for a β2-Adrenergic Receptor-Independent Protective Component

by Andria Kotsoni, Evelina Ioannou, Evangelia Barmparousi and Lefteris C. Zacharia

Curr. Issues Mol. Biol. 2026, 48(6), 571; https://doi.org/10.3390/cimb48060571 (registering DOI) - 29 May 2026

Abstract

β2-adrenergic receptor (β2-AR) agonists have been implicated in neuroprotection, yet their mechanisms remain obscure. We examined whether salbutamol (SA, short-acting) or formoterol (FO, long-acting) protect PC-12 cells from okadaic acid (OA), and evaluated receptor dependence, antioxidant capacity, and apoptotic signaling. Viability was quantified with crystal violet and MTT assays. OA reduced viability to approximately 60%, and SA or FO (0.1–10 µM) improved survival, which reached 76–83% at 10 µM (p < 0.05). β2-AR blockage with ICI-118,551, and ADRB2 mRNA knockdown did not abolish protection by FO or SA, suggesting a possible β2-AR-independent protective component. However, as knockdown was not confirmed at the protein level and signaling was not directly assessed, the evidence remains provisional. FO, but not SA, exhibited direct antioxidant activity in the DPPH assay, but both at 50 μΜ lowered H₂O₂-induced intracellular reactive oxygen species (from 167.9% to baseline, p < 0.05). Both compounds reduced the OA-induced expression of selected pro-apoptotic transcripts, although these mRNA data do not establish the functional inhibition of apoptosis. FO reduced fold change relative to untreated control from 5.8 to 2.6 for Bax, and 6.4 to 3.4 for Bak, whereas SA achieved a significant reduction only for Bax, from 5.8 to 4.4. Taken together, SA and FO offer a partial protection to PC-12 cells from OA cytotoxicity through pathways suggesting a β2-AR-independent protective component, with FO showing additional antioxidant properties and a reduced expression of selected pro-apoptotic transcripts. These findings provide preliminary evidence that select β2 agonists may exert cytoprotective effects that are consistent with, but do not establish, a receptor-independent component. These findings warrant further protein-level and functional validation. Full article

(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)

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19 pages, 5970 KB

Open AccessArticle

Exploring Hydroxytyrosol as a Promising Virucidal Agent: In Silico and In Vitro Insights into Enveloped Viruses

by Hanan El Ouadi, Zineb Rhazzar, Barbara Poddesu, Boutaina Addoum, Laila Benbacer, Franco Lori, Siham Fellahi, Davide De Forni, Omar Nyabi, Jean-Luc Gala, Elmostafa El Fahime, Saber Boutayeb, Lahcen Belyamani, Khalid Ennibi, Ouafaa Fassi Fehri and Nadia Touil

Curr. Issues Mol. Biol. 2026, 48(5), 481; https://doi.org/10.3390/cimb48050481 - 5 May 2026

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Abstract

The research investigates synthetic hydroxytyrosol (HT) antiviral properties against enveloped and non-enveloped viruses using in silico and in vitro methods. Molecular docking and ADMET analyses suggested favorable interactions of HT with ceramide and sphingomyelin (binding energies of −6.0 and −5.9 kcal/mol, respectively). Favorable predicted pharmacokinetics and safety profiles were also observed. In vitro tests provided preliminary evidence of the dose- and time-dependent virucidal effect of HT against several enveloped viruses, including HSV-1, West Nile virus, SARS-CoV-2 and various influenza A subtypes, which resulted in substantial viral load decreases at 1000 µg/mL. The viral titer of the measles virus decreased by 4.62 log₁₀ units during the 2 h of exposure. No virucidal activity was observed against the non-enveloped bovine rotavirus. Overall, these findings suggest that hydroxytyrosol may represent a promising candidate for further investigation as a virucidal agent, particularly against enveloped viruses. Full article

(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)

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18 pages, 5349 KB

Open AccessArticle

Discovery of Tyrosinase Inhibitors from Lysinibacillus sp. JNUCC 52 via Genome Mining, Secondary Metabolites Profiling, and In Silico Analysis

by Xuhui Liang, Yang Xu and Chang-Gu Hyun

Curr. Issues Mol. Biol. 2026, 48(3), 280; https://doi.org/10.3390/cimb48030280 - 5 Mar 2026

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Abstract

Tyrosinase is a key enzyme in melanin biosynthesis, and natural inhibitors have potential therapeutic and cosmetic applications. Lysinibacillus sp. JNUCC 52, a member of the Bacillaceae family, shows potential for producing bioactive secondary metabolites. However, the tyrosinase inhibitory potential of metabolites from this strain has not been previously reported. This study investigates its genomic features, secondary metabolites, and tyrosinase inhibitory activity to identify promising enzyme inhibitors. Integrated COG, GO, and KEGG annotation revealed a metabolically robust network supporting secondary metabolite biosynthesis. Chemical investigation of the ethyl acetate extract yielded five known compounds, among which cyclo(L-Pro-L-Leu) displayed the strongest tyrosinase inhibition (IC₅₀ = 79.5 ± 2.3 μM), whereas uracil showed weaker activity. In silico ADMET and drug-likeness analyses suggested favorable pharmacokinetic properties and compliance with major drug-likeness rules for cyclo(L-Pro-L-Leu). Molecular docking and molecular dynamics simulations demonstrated stable binding to mushroom tyrosinase (mTYR) and human TYRP1, supported by MM/GBSA and residue decomposition analyses identifying key stabilizing residues. Together, these results provide mechanistic insight into tyrosinase inhibition and highlight cyclo(L-Pro-L-Leu) as a minimal lead-like scaffold, while establishing strain JNUCC 52 as a promising microbial source of bioactive metabolites. Full article

(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)

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26 pages, 2757 KB

Open AccessArticle

Novel Synthetic Steroid Derivatives: Target Prediction and Biological Evaluation of Antiandrogenic Activity

by David Calderón Guzmán, Norma Osnaya Brizuela, Hugo Juárez Olguín, Maribel Ortiz Herrera, Armando Valenzuela Peraza, Ernestina Hernández Garcia, Alejandra Chávez Riveros, Sarai Calderón Morales, Alberto Rojas Ochoa, Aylin Silva Ortiz, Rebeca Santes Palacios, Víctor Manuel Dorado Gonzalez and Diego García Ortega

Curr. Issues Mol. Biol. 2025, 47(12), 1059; https://doi.org/10.3390/cimb47121059 - 17 Dec 2025

Cited by 1 | Viewed by 1032

Abstract

Background: Two natural steroids derived from cholesterol pathways are testosterone and progesterone, androgen and antiandrogen receptor binding. Steroid androgen antagonists can be prescribed to treat an array of diseases and disorders such as gender dysphoria. In men, androgen antagonists are frequently used to treat prostate cancer and hyperplasia. Sex hormones regulate the expression of the viral receptors in COVID-19 progression, and these hormones may act as a metabolic signal-mediating response to changes in glucose and Reactive Oxygen Species (ROS). The objective of the present study is to use artificial intelligence (AI) applications in healthcare to predict the targets and to assess biological assays of novel steroid derivatives prepared in house from the commercially available 16-dehydropregnenolone acetate (DPA^®) aimed at achieving the metabolic stability of glucose and steroid brain homeostasis. This suggests the introduction of aromatic or aliphatic structures in the steroid B-ring and D-ring. This is important since the roles of 5α-reductase and ROS in brain control of glucose and novel steroids homeostasis remain unclear. Methods: A tool prediction was used as a tuned algorithm, with the novel steroid derivatives data in web interface to carry out their pharmacological evaluation. The new steroidal derivatives were determined with neuroprotection effect using the select biomarkers of oxidative stress on induced hypoglycemic male rat brain and liver. The enzyme kinetics was established by the inhibition of the 5α-reductase enzyme on the brain myelin. Results: We used novel chemical structures to order the information of a Swiss data bank that allow target predictions. Biological assays suggest that steroid derivatives with an electrophilic center can interact more efficiently with the 5α-reductase enzyme, and by this way, induce neuroprotection in hypoglycemia model. All compounds were synthesized with a yield of 30–80% and evaluated with tool target prediction to understand the molecular mechanisms underlying a given phenotype or bioactivity and to rationalize possible favorable or unfavorable side effects, as well as to predict off-targets of known molecules and to clear the way for drug repurposing. Apart, they turned out to be good inhibitors for the 5α-reductase enzyme. Conclusions: The probed efficacy of these novel steroids with respect to spironolactone control appears to be a promising compound for future hormonal therapy with neuroprotection activity in glucose disorder status. However, further research with clinically meaningful endpoints is needed to optimize the use of androgen antagonists in these hormonal therapies in COVID-19 progression. Full article

(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)

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16 pages, 2282 KB

Open AccessArticle

Activation of Angiogenic TGF-β1 by Salbutamol Enhances Wound Contraction and Improves Healing in a Streptozotocin-Induced Diabetic Rat Model

by Promise M. Emeka, Abdulaziz K. Al Mouslem, Hussien Almutawa, Malek Albandri, Hussain Alhmoud, Mohammed Alhelal, Zakaria Alhassan and Abdullah Alhamar

Curr. Issues Mol. Biol. 2025, 47(10), 820; https://doi.org/10.3390/cimb47100820 - 3 Oct 2025

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Abstract

Wound healing is impaired under diabetic conditions due to reduced angiogenesis, thereby increasing the risk of wound-healing complications. Studies have shown that inhibition of α- and β-adrenoceptors delays wound healing. This study investigates the effects of topical salbutamol (TS) on STZ-induced diabetic wound healing in rats. The rats were divided into two initial groups: non-diabetic and diabetic. Diabetes mellitus was induced in the second group with STZ (65 mg/kg). Excision wounds were inflicted on the dorsal thoracic region, 1–1.5 cm away from the vertebral column on either side, following anesthesia on all groups. Group 2 was subdivided into untreated diabetic wounds, low-dose-TS-treated diabetic wounds (6.25 mg/mL), medium-dose-TS-treated diabetic wounds (12.5 mg/mL), and high-dose-TS-treated diabetic wounds (25 mg/mL), and were monitored for 14 days. Percentage wound contraction and the time required for complete wound closure were observed and recorded. In addition, oxidative stress and inflammatory markers such as NO, CRP, MPO, TGF-β1, TNF-α, IL-6, IL-1β, NO, and hexosamine were estimated in wound exudates and tissue over 14 days. TS treatment resulted in 100% wound contraction in all treated wounds within 14 days compared to untreated non-diabetic and diabetic wounds. Increased NO, TGF-β1, and hexosamine activity was observed in TS-treated wounds when compared to untreated diabetic wounds. In addition, TS treatment decreased the activity of IL-1β, TNF-α, IL-6, CRP, and MPO, all of which were elevated in the untreated diabetic wounds. The current study shows that the application of TS significantly improved diabetic wound contraction and aided the healing process. Angiogenic markers, such as TGF-β1 and NO, were prominently increased, supporting the role of sympathetic nerve stimulation in angiogenesis. Full article

(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)

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Review

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36 pages, 5383 KB

Open AccessReview

Unraveling Translational Insights into Systemic Multi-Organ Toxicity of Cytosine Arabinoside (Ara-C): A Systematic Review of Preclinical Animal Evidence

by Ioannis Konstantinidis, Sophia Tsokkou, Antonios Keramas, Kali Makedou, Eleni Gavriilaki, Georgios Delis and Theodora Papamitsou

Curr. Issues Mol. Biol. 2026, 48(1), 4; https://doi.org/10.3390/cimb48010004 - 19 Dec 2025

Viewed by 919

Abstract

Background/Objectives: Cytarabine (Ara-C) remains central to acute myeloid leukemia therapy but is limited by unpredictable systemic toxicities. Preclinical studies have long documented multi-organ injury, yet findings remain fragmented. This systematic review synthesizes animal evidence to clarify the spectrum, dose–response patterns, and mechanisms of cytarabine-induced toxicity. Methods: Following PRISMA 2020 guidelines and PROSPERO registration (CRD420251081384), a comprehensive search of PubMed, MEDLINE, Scopus, Cochrane Library and Embase identified eligible in vivo animal studies. Data extraction covered animal models, dosing regimens, routes of administration, histopathological and biochemical endpoints and mechanistic findings. Risk of bias and study quality were assessed using SYRCLE’s tool, CAMARADES checklist and an adapted Newcastle–Ottawa Scale, with reporting benchmarked against ARRIVE 2.0. Results: Eighty-one studies (1964–2024) were included. Cytarabine produced dose- and regimen-dependent toxicities across multiple organs. Neurotoxicity was most frequently reported, followed by intestinal mucositis, ocular injury, alopecia, hepatotoxicity, nephrotoxicity, and developmental anomalies. Mechanistic analyses consistently implicated oxidative stress, inflammatory cascades, apoptosis, and epigenetic dysregulation. Study quality was moderate, with frequent deficiencies in randomization, blinding, and sample-size justification, raising concerns about reproducibility. Cardiotoxicity, despite clinical relevance, was virtually absent from preclinical evaluation. Conclusions: Preclinical evidence suggests cytarabine’s systemic toxicity as a multifactorial process extending beyond rapidly proliferating tissues. While animal studies provide mechanistic insights, methodological weaknesses and translational gaps limit predictive value. Future research must adopt rigorous design, systematically assess underexplored toxicities, and integrate molecular profiling to identify biomarkers and protective strategies. Full article

(This article belongs to the Special Issue Novel Pharmacological Strategies and Molecular Mechanisms in Nonclinical Research)

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