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Keywords = protein–drug interactions

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23 pages, 3665 KiB  
Communication
Drug Repurposing for Kala-Azar
by Biljana Arsić, Budimir S. Ilić, Andreas Maier, Michael Hartung, Jovana Janjić, Jelena Milićević and Jan Baumbach
Pharmaceutics 2025, 17(8), 1021; https://doi.org/10.3390/pharmaceutics17081021 - 6 Aug 2025
Abstract
Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated [...] Read more.
Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article
(This article belongs to the Section Drug Targeting and Design)
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15 pages, 271 KiB  
Article
Are We Considering All the Potential Drug–Drug Interactions in Women’s Reproductive Health? A Predictive Model Approach
by Pablo Garcia-Acero, Ismael Henarejos-Castillo, Francisco Jose Sanz, Patricia Sebastian-Leon, Antonio Parraga-Leo, Juan Antonio Garcia-Velasco and Patricia Diaz-Gimeno
Pharmaceutics 2025, 17(8), 1020; https://doi.org/10.3390/pharmaceutics17081020 - 6 Aug 2025
Abstract
Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient [...] Read more.
Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient management, avoid drug combinations that can negatively affect patient care, and exploit potential synergistic combinations to improve current therapies in women’s healthcare. Methods: A DDI prediction model was built to describe relevant drug combinations affecting reproductive treatments. Approved drug features (chemical structure of drugs, side effects, targets, enzymes, carriers and transporters, pathways, protein–protein interactions, and interaction profile fingerprints) were obtained. A unified predictive score revealed unknown DDIs between reproductive and commonly used drugs and their associated clinical effects on reproductive health. The performance of the prediction model was validated using known DDIs. Results: This prediction model accurately predicted known interactions (AUROC = 0.9876) and identified 2991 new DDIs between 192 drugs used in different female reproductive conditions and other drugs used to treat unrelated conditions. These DDIs included 836 between drugs used for in vitro fertilization. Most new DDIs involved estradiol, acetaminophen, bupivacaine, risperidone, and follitropin. Follitropin, bupivacaine, and gonadorelin had the highest discovery rate (42%, 32%, and 25%, respectively). Some were expected to improve current therapies (n = 23), while others would cause harmful effects (n = 11). We also predicted twelve DDIs between oral contraceptives and HIV drugs that could compromise their efficacy. Conclusions: These results show the importance of DDI studies aimed at identifying those that might compromise or improve their efficacy, which could lead to personalizing female reproductive therapies. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
17 pages, 2994 KiB  
Article
Structural Insights and Calcium-Switching Mechanism of Fasciola hepatica Calcium-Binding Protein FhCaBP4
by Byeongmin Shin, Seonha Park, Ingyo Park, Hongchul Shin, Kyuhyeon Bang, Sulhee Kim and Kwang Yeon Hwang
Int. J. Mol. Sci. 2025, 26(15), 7584; https://doi.org/10.3390/ijms26157584 - 5 Aug 2025
Abstract
Fasciola hepatica remains a global health and economic concern, and treatment still relies heavily on triclabendazole. At the parasite–host interface, F. hepatica calcium-binding proteins (FhCaBPs) have a unique EF-hand/DLC-like domain fusion found only in trematodes. This makes it a parasite-specific target for small [...] Read more.
Fasciola hepatica remains a global health and economic concern, and treatment still relies heavily on triclabendazole. At the parasite–host interface, F. hepatica calcium-binding proteins (FhCaBPs) have a unique EF-hand/DLC-like domain fusion found only in trematodes. This makes it a parasite-specific target for small compounds and vaccinations. To enable novel therapeutic strategies, we report the first elevated-resolution structure of a full-length FhCaBP4. The apo structure was determined at 1.93 Å resolution, revealing a homodimer architecture that integrates an N-terminal, calmodulin-like, EF-hand pair with a C-terminal dynein light chain (DLC)-like domain. Structure-guided in silico mutagenesis identified a flexible, 16-residue β4–β5 loop (LTGSYWMKFSHEPFMS) with an FSHEPF core that demonstrates greater energetic variability than its FhCaBP2 counterpart, likely explaining the distinct ligand-binding profiles of these paralogs. Molecular dynamics simulations and AlphaFold3 modeling suggest that EF-hand 2 acts as the primary calcium-binding site, with calcium coordination inducing partial rigidification and modest expansion of the protein structure. Microscale thermophoresis confirmed calcium as the major ligand, while calmodulin antagonists bound with lower affinity and praziquantel demonstrated no interaction. Thermal shift assays revealed calcium-dependent stabilization and a merger of biphasic unfolding transitions. These results suggest that FhCaBP4 functions as a calcium-responsive signaling hub, with an allosterically coupled EF-hand–DLC interface that could serve as a structurally tractable platform for drug targeting in trematodes. Full article
(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: Third Edition)
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12 pages, 806 KiB  
Proceeding Paper
Enterococcus faecalis Biofilm: A Clinical and Environmental Hazard
by Bindu Sadanandan and Kavyasree Marabanahalli Yogendraiah
Med. Sci. Forum 2025, 35(1), 5; https://doi.org/10.3390/msf2025035005 - 5 Aug 2025
Abstract
This review explores the biofilm architecture and drug resistance of Enterococcus faecalis in clinical and environmental settings. The biofilm in E. faecalis is a heterogeneous, three-dimensional, mushroom-like or multilayered structure, characteristically forming diplococci or short chains interspersed with water channels for nutrient exchange [...] Read more.
This review explores the biofilm architecture and drug resistance of Enterococcus faecalis in clinical and environmental settings. The biofilm in E. faecalis is a heterogeneous, three-dimensional, mushroom-like or multilayered structure, characteristically forming diplococci or short chains interspersed with water channels for nutrient exchange and waste removal. Exopolysaccharides, proteins, lipids, and extracellular DNA create a protective matrix. Persister cells within the biofilm contribute to antibiotic resistance and survival. The heterogeneous architecture of the E. faecalis biofilm contains both dense clusters and loosely packed regions that vary in thickness, ranging from 10 to 100 µm, depending on the environmental conditions. The pathogenicity of the E. faecalis biofilm is mediated through complex interactions between genes and virulence factors such as DNA release, cytolysin, pili, secreted antigen A, and microbial surface components that recognize adhesive matrix molecules, often involving a key protein called enterococcal surface protein (Esp). Clinically, it is implicated in a range of nosocomial infections, including urinary tract infections, endocarditis, and surgical wound infections. The biofilm serves as a nidus for bacterial dissemination and as a reservoir for antimicrobial resistance. The effectiveness of first-line antibiotics (ampicillin, vancomycin, and aminoglycosides) is diminished due to reduced penetration, altered metabolism, increased tolerance, and intrinsic and acquired resistance. Alternative strategies for biofilm disruption, such as combination therapy (ampicillin with aminoglycosides), as well as newer approaches, including antimicrobial peptides, quorum-sensing inhibitors, and biofilm-disrupting agents (DNase or dispersin B), are also being explored to improve treatment outcomes. Environmentally, E. faecalis biofilms contribute to contamination in water systems, food production facilities, and healthcare environments. They persist in harsh conditions, facilitating the spread of multidrug-resistant strains and increasing the risk of transmission to humans and animals. Therefore, understanding the biofilm architecture and drug resistance is essential for developing effective strategies to mitigate their clinical and environmental impact. Full article
(This article belongs to the Proceedings of The 4th International Electronic Conference on Antibiotics)
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17 pages, 3151 KiB  
Article
Towards a Consensus for the Analysis and Exchange of TFA as a Counterion in Synthetic Peptides and Its Influence on Membrane Permeation
by Vanessa Erckes, Alessandro Streuli, Laura Chamera Rendueles, Stefanie Dorothea Krämer and Christian Steuer
Pharmaceuticals 2025, 18(8), 1163; https://doi.org/10.3390/ph18081163 - 5 Aug 2025
Abstract
Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as [...] Read more.
Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as a cleavage agent and ion-pairing reagent, respectively, resulting in peptides being obtained as TFA salts. Although TFA has excellent properties for peptide production, numerous studies highlight the negative impact of using peptides from TFA salts in biological assays. Methods: Investigated peptides were synthesized via SPPS and the TFA counterion was exchanged for Cl via freeze-drying in different concentrations of HCl. Detection and quantification of residual TFA were carried out via FT-IR, 19F-NMR, and HPLC using an evaporative light-scattering detector (ELSD). A liposomal fluorescence assay was used to test for the influence of the counterion on the peptides’ passive membrane permeability. Results: All TFA detection methods were successfully validated according to ICH guidelines. TFA removal with 10 mM HCl was determined to be the optimal condition. No impact on peptide purity was observed at all HCl concentrations. Influences on permeability coefficients depending on peptide sequence and salt form were found. Conclusions: This study presents a systematic investigation of the removal of TFA counterions from synthetic peptides and their replacement with Cl counterions. Detected counterion contents were used to understand the impact of sequence differences, especially positive charges, on the amount and potential localization of counterions. Our findings emphasize the importance of counterion quantification and specification in assays with synthetic peptides. Full article
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23 pages, 9844 KiB  
Article
Mechanistic Exploration of Aristolochic Acid I-Induced Hepatocellular Carcinoma: Insights from Network Toxicology, Machine Learning, Molecular Docking, and Molecular Dynamics Simulation
by Tiantaixi Tu, Tongtong Zheng, Hangqi Lin, Peifeng Cheng, Ye Yang, Bolin Liu, Xinwang Ying and Qingfeng Xie
Toxins 2025, 17(8), 390; https://doi.org/10.3390/toxins17080390 - 5 Aug 2025
Viewed by 38
Abstract
This study explores how aristolochic acid I (AAI) drives hepatocellular carcinoma (HCC). We first employ network toxicology and machine learning to map the key molecular target genes. Next, our research utilizes molecular docking to evaluate how AAI binds to these targets, and finally [...] Read more.
This study explores how aristolochic acid I (AAI) drives hepatocellular carcinoma (HCC). We first employ network toxicology and machine learning to map the key molecular target genes. Next, our research utilizes molecular docking to evaluate how AAI binds to these targets, and finally confirms the stability and dynamics of the resulting complexes through molecular dynamics simulations. We identified 193 overlapping target genes between AAI and HCC through databases such as PubChem, OMIM, and ChEMBL. Machine learning algorithms (SVM-RFE, random forest, and LASSO regression) were employed to screen 11 core genes. LASSO serves as a rapid dimension-reduction tool, SVM-RFE recursively eliminates the features with the smallest weights, and Random Forest achieves ensemble learning through decision trees. Protein–protein interaction networks were constructed using Cytoscape 3.9.1, and key genes were validated through GO and KEGG enrichment analyses, an immune infiltration analysis, a drug sensitivity analysis, and a survival analysis. Molecular-docking experiments showed that AAI binds to each of the core targets with a binding affinity stronger than −5 kcal mol−1, and subsequent molecular dynamics simulations verified that these complexes remain stable over time. This study determined the potential molecular mechanisms underlying AAI-induced HCC and identified key genes (CYP1A2, ESR1, and AURKA) as potential therapeutic targets, providing valuable insights for developing targeted strategies to mitigate the health risks associated with AAI exposure. Full article
(This article belongs to the Section Plant Toxins)
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20 pages, 1772 KiB  
Review
The Binding and Effects of Boron-Containing Compounds on G Protein-Coupled Receptors: A Scoping Review
by José M. Santiago-Quintana, Alina Barquet-Nieto, Bhaskar C. Das, Rafael Barrientos-López, Melvin N. Rosalez, Ruth M. Lopez-Mayorga and Marvin A. Soriano-Ursúa
Receptors 2025, 4(3), 15; https://doi.org/10.3390/receptors4030015 - 5 Aug 2025
Viewed by 74
Abstract
Boron-containing compounds (BCCs) have emerged as potential drugs. Their drug-like effects are mainly explained by their mechanisms of action in enzymes. Nowadays, some experimental data support the effects of specific BCCs on GPCRs, provided there are crystal structures that show them bound to [...] Read more.
Boron-containing compounds (BCCs) have emerged as potential drugs. Their drug-like effects are mainly explained by their mechanisms of action in enzymes. Nowadays, some experimental data support the effects of specific BCCs on GPCRs, provided there are crystal structures that show them bound to G protein-coupled receptors (GPCRs). Some BCCs are recognized as potential ligands of GPCRs—the drug targets of many diseases. Objective: The aim of this study was to collecte up-to-date data on the interactions of BCCs with GPCRs. Methods: Data were collected from the National Center of Biotechnology Information, PubMed, Global Health, Embase, the Web of Science, and Google Scholar databases and reviewed. Results: Some experimental reports support the interactions of BCCs with several GPCRs, acting as their labels, agonists, or antagonists. These interactions can be inferred based on in silico and in vitro results if there are no available crystal structures for validating them. Conclusions: The actions of BCCs on GPCRs are no longer hypothetical, as the existing evidence supports BCCs’ interactions with and actions on GPCRs. Full article
(This article belongs to the Collection Receptors: Exceptional Scientists and Their Expert Opinions)
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28 pages, 2282 KiB  
Article
From Hue to Health: Exploring the Therapeutic Potential of Plant-Pigment-Enriched Extracts
by Azza SalahEldin El-Demerdash, Amira E. Sehim, Abeer Altamimi, Hanan Henidi, Yasmin Mahran and Ghada E. Dawwam
Microorganisms 2025, 13(8), 1818; https://doi.org/10.3390/microorganisms13081818 - 4 Aug 2025
Viewed by 213
Abstract
The escalating global challenges of antimicrobial resistance (AMR) and cancer necessitate innovative therapeutic solutions from natural sources. This study investigated the multifaceted therapeutic potential of pigment-enriched plant extracts. We screened diverse plant extracts for antimicrobial and antibiofilm activity against multidrug-resistant bacteria and fungi. [...] Read more.
The escalating global challenges of antimicrobial resistance (AMR) and cancer necessitate innovative therapeutic solutions from natural sources. This study investigated the multifaceted therapeutic potential of pigment-enriched plant extracts. We screened diverse plant extracts for antimicrobial and antibiofilm activity against multidrug-resistant bacteria and fungi. Hibiscus sabdariffa emerged as the most promising, demonstrating potent broad-spectrum antimicrobial and significant antibiofilm activity. Sub-inhibitory concentrations of H. sabdariffa robustly downregulated essential bacterial virulence genes and suppressed aflatoxin gene expression. Comprehensive chemical profiling via HPLC identified major anthocyanin glucosides, while GC-MS revealed diverse non-pigment bioactive compounds, including fatty acids and alcohols. Molecular docking suggested favorable interactions of key identified compounds (Cyanidin-3-O-glucoside and 1-Deoxy-d-arabitol) with E. coli outer membrane protein A (OmpA), indicating potential antiadhesive and antimicrobial mechanisms. Furthermore, H. sabdariffa exhibited selective cytotoxicity against MCF-7 breast cancer cells. These findings establish H. sabdariffa pigment-enriched extract as a highly promising, multi-functional source of novel therapeutics, highlighting its potential for simultaneously addressing drug resistance and cancer challenges through an integrated chemical, biological, and computational approach. Full article
(This article belongs to the Special Issue Advanced Research on Antimicrobial Activity of Natural Products)
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27 pages, 6689 KiB  
Article
Steroidal Oximes and Cervical Cancer: An In Silico Mechanistic Pathway Approach
by Carlos Antonio Sánchez-Valdeolivar, Alan Carrasco-Carballo, Jorge Organista-Nava, Jesús Sandoval-Ramírez and Berenice Illades-Aguiar
Sci. Pharm. 2025, 93(3), 36; https://doi.org/10.3390/scipharm93030036 - 4 Aug 2025
Viewed by 284
Abstract
Cervical cancer affects 661,000 women worldwide; as a result, new treatment alternatives are still being sought, with steroid oximes being the most prominent. However, the molecular targets where steroid oximes exert their anticancer activity remain unknown. In this study, reports of the activity [...] Read more.
Cervical cancer affects 661,000 women worldwide; as a result, new treatment alternatives are still being sought, with steroid oximes being the most prominent. However, the molecular targets where steroid oximes exert their anticancer activity remain unknown. In this study, reports of the activity in cell lines were obtained, and the targets associated with cervical cancer were identified using bioinformatics tools, based on two- and three-dimensional structural similarity analysis. Subsequently, molecular targets were analyzed via molecular docking using Schrödinger software v.2022-4 to determine their effects compared with reference drugs. Interrelated proteins and isolated proteins were observed, suggesting both the multi-target and single-target activity of steroid oximes. The analysis revealed that 60% of the 42 identified proteins had previously been reported in the literature and were associated with cervical cancer in processes related to cell proliferation, invasion, migration, and apoptosis. Among them, SRC, IGF1R, and MDM2 showed feasibility for multi-target interaction, which is consistent with the lower IC50 values reported for oximes in cervical cancer cell lines (HeLa and CaSki). This finding suggests that steroid oximes are multi-target molecules that can inhibit the proteins associated with cervical cancer, particularly through the IGF1R, MDM2, and SRC pathways related to cell proliferation and apoptosis, serving as a guideline for the future design of new steroidal oximes. Full article
(This article belongs to the Topic Bioinformatics in Drug Design and Discovery—2nd Edition)
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21 pages, 3431 KiB  
Article
Synthesis and Antibacterial Evaluation of an Indole Triazole Conjugate with In Silico Evidence of Allosteric Binding to Penicillin-Binding Protein 2a
by Vidyasrilekha Sanapalli, Bharat Kumar Reddy Sanapalli and Afzal Azam Mohammed
Pharmaceutics 2025, 17(8), 1013; https://doi.org/10.3390/pharmaceutics17081013 - 3 Aug 2025
Viewed by 312
Abstract
Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial [...] Read more.
Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial cell wall biosynthesis. Objectives: The objective was to design and characterize a novel small-molecule inhibitor targeting PBP2a as a strategy to combat MRSA. Methods: We synthesized a new indole triazole conjugate (ITC) using eco-friendly and click chemistry approaches. In vitro antibacterial tests were performed against a panel of strains to evaluate the ITC antibacterial potential. Further, a series of in silico evaluations like molecular docking, MD simulations, free energy landscape (FEL), and principal component analysis (PCA) using the crystal structure of PBP2a (PDB ID: 4CJN), in order to predict the mechanism of action, binding mode, structural stability, and energetic profile of the 4CJN-ITC complex. Results: The compound ITC exhibited noteworthy antibacterial activity, which effectively inhibited the selected strains. Binding score and energy calculations demonstrated high affinity of ITC for the allosteric site of PBP2a and significant interactions responsible for complex stability during MD simulations. Further, FEL and PCA provided insights into the conformational behavior of ITC. These results gave the structural clues for the inhibitory action of ITC on the PBP2a. Conclusions: The integrated in vitro and in silico studies corroborate the potential of ITC as a promising developmental lead targeting PBP2a in MRSA. This study demonstrates the potential usage of rational drug design approaches in addressing therapeutic needs related to ABR. Full article
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21 pages, 2399 KiB  
Review
Various Approaches Employed to Enhance the Bioavailability of Antagonists Interfering with the HMGB1/RAGE Axis
by Harbinder Singh
Int. J. Transl. Med. 2025, 5(3), 35; https://doi.org/10.3390/ijtm5030035 - 2 Aug 2025
Viewed by 230
Abstract
High-mobility group box 1 (HMGB1) is a nuclear protein that can interact with a transmembrane cell surface receptor for advanced glycation end products (RAGEs) and mediates the inflammatory pathways that lead to various pathological conditions like cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders. [...] Read more.
High-mobility group box 1 (HMGB1) is a nuclear protein that can interact with a transmembrane cell surface receptor for advanced glycation end products (RAGEs) and mediates the inflammatory pathways that lead to various pathological conditions like cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders. Blocking the HMGB1/RAGE axis using various small synthetic or natural molecules has been proven to be an effective therapeutic approach to treating these inflammatory conditions. However, the low water solubility of these pharmacoactive molecules limits their clinical use. Pharmaceutically active molecules with low solubility and bioavailability in vivo convey a higher risk of failure for drug development and drug innovation. The pharmacokinetic and pharmacodynamics parameters of these compounds are majorly affected by their solubility. Enhancement of the bioavailability and solubility of drugs is a significant challenge in the area of pharmaceutical formulations. This review mainly describes various technologies utilized to improve the bioavailability of synthetic or natural molecules which have been particularly used in various inflammatory conditions acting specifically through the HMGB1/RAGE pathway. Full article
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36 pages, 4836 KiB  
Article
Harnessing the Hepatoprotective and Nephroprotective Potential of Nigella sativa Fractions via per os Administration in CCl4-Intoxicated Wistar Rats: A Mixed Approach
by Mohammed Dalli, Nour Elhouda Daoudi, Salah-eddine Azizi, Mohammed Roubi, Ilyass Alami Merrouni, Faiza Souna, Mohammed Choukri, Bonglee Kim and Nadia Gseyra
Pharmaceuticals 2025, 18(8), 1147; https://doi.org/10.3390/ph18081147 - 1 Aug 2025
Viewed by 137
Abstract
Background: Nigella sativa, known as black cumin, is traditionally used to treat various illnesses. Objective: The current study aims to investigate the potential hepatoprotective and nephroprotective effect of black cumin fractions via per os route in CCl4-intoxicated Wistar rats. [...] Read more.
Background: Nigella sativa, known as black cumin, is traditionally used to treat various illnesses. Objective: The current study aims to investigate the potential hepatoprotective and nephroprotective effect of black cumin fractions via per os route in CCl4-intoxicated Wistar rats. This study used a computational approach to assess the interaction of bioactive compounds with key proteins (CYP P450 3E1, TNF-α, and Cox-2). Methods:Wistar rats were treated with CCl4 to induce liver injury and with different Nigella sativa fractions (250 mg/Kg) or Sylimarin (50 mg/Kg). Liver and kidney functions were assessed through biochemical markers, hepatic glycogen, malondialdehyde levels, molecular docking, and ADMET analysis to evaluate drug-likeliness. Results: The results revealed that intoxication with CCl4 induced an elevation in different liver and kidney biochemical parameters such as (ALT, AST, creatinine, urea...) indicating kidney and hepatic toxicity. However, treatment with different Nigella sativa fractions showed a significant improvement in animal body weight and significant amelioration of biochemical markers indicating a protective potential of these fractions against CCl4-induced intoxication. Furthermore, the molecular docking approach demonstrated high binding affinity with the target proteins. Conclusions: These current findings shed light on the therapeutic potential of Nigella sativa fractions as a promising protective agent of the liver and kidney against CCl4 intoxication. Full article
(This article belongs to the Section Natural Products)
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21 pages, 6211 KiB  
Article
In Silico and In Vitro Potential Antifungal Insights of Insect-Derived Peptides in the Management of Candida sp. Infections
by Catarina Sousa, Alaka Sahoo, Shasank Sekhar Swain, Payal Gupta, Francisco Silva, Andreia S. Azevedo and Célia Fortuna Rodrigues
Int. J. Mol. Sci. 2025, 26(15), 7449; https://doi.org/10.3390/ijms26157449 - 1 Aug 2025
Viewed by 242
Abstract
The worldwide increase in antifungal resistance, particularly in Candida sp., requires the exploration of novel therapeutic agents. Natural compounds have been a rich source of antimicrobial molecules, where peptides constitute the class of the most bioactive components. Therefore, this study looks into the [...] Read more.
The worldwide increase in antifungal resistance, particularly in Candida sp., requires the exploration of novel therapeutic agents. Natural compounds have been a rich source of antimicrobial molecules, where peptides constitute the class of the most bioactive components. Therefore, this study looks into the target-specific binding efficacy of insect-derived antifungal peptides (n = 37) as possible alternatives to traditional antifungal treatments. Using computational methods, namely the HPEPDOCK and HDOCK platforms, molecular docking was performed to evaluate the interactions between selected key fungal targets, lanosterol 14-demethylase, or LDM (PDB ID: 5V5Z), secreted aspartic proteinase-5, or Sap-5 (PDB ID: 2QZX), N-myristoyl transferase, or NMT (PDB ID: 1NMT), and dihydrofolate reductase, or DHFR, of C. albicans. The three-dimensional peptide structure was modelled through the PEP-FOLD 3.5 tool. Further, we predicted the physicochemical properties of these peptides through the ProtParam and PEPTIDE 2.0 tools to assess their drug-likeness and potential for therapeutic applications. In silico results show that Blap-6 from Blaps rhynchopeter and Gomesin from Acanthoscurria gomesiana have the most antifungal potential against all four targeted proteins in Candida sp. Additionally, a molecular dynamics simulation study of LDM-Blap-6 was carried out at 100 nanoseconds. The overall predictions showed that both have strong binding abilities and are good candidates for drug development. In in vitro studies, Gomesin achieved complete biofilm eradication in three out of four Candida species, while Blap-6 showed moderate but consistent reduction across all species. C. tropicalis demonstrated relative resistance to complete eradication by both peptides. The present study provides evidence to support the antifungal activity of certain insect peptides, with potential to be used as alternative drugs or as a template for a new synthetic or modified peptide in pursuit of effective therapies against Candida spp. Full article
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14 pages, 1399 KiB  
Article
GSTM5 as a Potential Biomarker for Treatment Resistance in Prostate Cancer
by Patricia Porras-Quesada, Lucía Chica-Redecillas, Beatriz Álvarez-González, Francisco Gutiérrez-Tejero, Miguel Arrabal-Martín, Rosa Rios-Pelegrina, Luis Javier Martínez-González, María Jesús Álvarez-Cubero and Fernando Vázquez-Alonso
Biomedicines 2025, 13(8), 1872; https://doi.org/10.3390/biomedicines13081872 - 1 Aug 2025
Viewed by 218
Abstract
Background/Objectives: Androgen deprivation therapy (ADT) is widely used to manage prostate cancer (PC), but the emergence of treatment resistance remains a major clinical challenge. Although the GST family has been implicated in drug resistance, the specific role of GSTM5 remains poorly understood. [...] Read more.
Background/Objectives: Androgen deprivation therapy (ADT) is widely used to manage prostate cancer (PC), but the emergence of treatment resistance remains a major clinical challenge. Although the GST family has been implicated in drug resistance, the specific role of GSTM5 remains poorly understood. This study investigates whether GSTM5, alone or in combination with clinical variables, can improve patient stratification based on the risk of early treatment resistance. Methods: In silico analyses were performed to examine GSTM5’s role in protein interactions, molecular pathways, and gene expression. The rs3768490 polymorphism was genotyped in 354 patients with PC, classified by ADT response. Descriptive analysis and logistic regression models were applied to evaluate associations between genotype, clinical variables, and ADT response. GSTM5 expression related to the rs3768490 genotype and ADT response was also analyzed in 129 prostate tissue samples. Results: The T/T genotype of rs3768490 was significantly associated with a lower likelihood of early ADT resistance in both individual (p = 0.0359, Odd Ratios (OR) = 0.18) and recessive models (p = 0.0491, OR = 0.21). High-risk classification according to D’Amico was strongly associated with early progression (p < 0.0004; OR > 5.4). Combining genotype and clinical risk improved predictive performance, highlighting their complementary value in stratifying patients by treatment response. Additionally, GSTM5 expression was slightly higher in T/T carriers, suggesting a potential protective role against ADT resistance. Conclusions: The T/T genotype of rs3768490 may protect against ADT resistance by modulating GSTM5 expression in PC. These preliminary findings highlight the potential of integrating genetic biomarkers into clinical models for personalized treatment strategies, although further studies are needed to validate these observations. Full article
(This article belongs to the Special Issue Molecular Biomarkers of Tumors: Advancing Genetic Studies)
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12 pages, 2497 KiB  
Article
Atomistic-Level Structural Insight into Vespa Venom (Ves a 1) and Lipid Membrane Through the View of Molecular Dynamics Simulation
by Nawanwat Chainuwong Pattaranggoon, Withan Teajaroen, Sakda Daduang, Supot Hannongbua, Thanyada Rungrotmongkol and Varomyalin Tipmanee
Toxins 2025, 17(8), 387; https://doi.org/10.3390/toxins17080387 - 31 Jul 2025
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Abstract
This study used all-atom molecular dynamics simulations to investigate the structural dynamics of Ves a 1, a phospholipase from Vespa affinis venom, and its interactions within a lipid membrane environment, both alone and in the presence of the inhibitor voxilaprevir. Simulations conducted over [...] Read more.
This study used all-atom molecular dynamics simulations to investigate the structural dynamics of Ves a 1, a phospholipase from Vespa affinis venom, and its interactions within a lipid membrane environment, both alone and in the presence of the inhibitor voxilaprevir. Simulations conducted over 1 µs for triplicate runs demonstrated system stability and convergence of structural properties. Our findings reveal that Ves a 1 engages in dynamic interactions with the lipid bilayer, involving key regions such as its lids, catalytic triad, and auxiliary site. The presence of voxilaprevir was observed to subtly alter these membrane interaction patterns and influence the enzyme’s catalytic area, reflecting the inhibitor’s impact within its physiological context. These results emphasize the crucial role of the lipid bilayer in shaping enzyme function and highlight voxilaprevir as a promising candidate for further inhibitor development, offering vital insights for rational drug design targeting membrane-associated proteins. Full article
(This article belongs to the Special Issue Venoms and Drugs)
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