Search Results (805)

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

Neglected diseases significantly impact the world, and there is a lack of effective treatments, requiring therapeutic alternatives. Thus, the study of the phytochemical and schistosomicidal activity evaluation of Copaifera oblongifolia leaves’ crude extract was conducted. The quercitrin (1) and afzelin (2) were isolated from the crude extract. In the in vitro schistosomicidal activity test, the isolated compounds demonstrated promising results, with 75% mortality at a concentration of 12.5 µM after 72 h. Molecular docking calculations indicated that compounds 1 and 2 could potentially interact with the amino acids of the FAD binding site in the TGR enzyme, a crucial enzyme for the survival of Schistosoma mansoni. These interactions could have binding energies comparable to praziquantel, a preferred drug for treating schistosomiasis. Therefore, in silico and in vitro investigations are crucial for developing new studies that can reveal the antiparasitic potential of compounds of plant origin. Full article

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

Leishmaniasis is an infectious disease common in tropical and subtropical regions worldwide. This study aimed to develop a topical meglumine antimoniate gel (MA-gel) for the treatment of cutaneous leishmaniasis. The MA-gel was characterized in terms of morphology, pH, swelling, porosity, rheology, and thermal properties by differential scanning calorimetry (DSC). Biopharmaceutical evaluation included in vitro drug release and ex vivo skin permeation. Safety was evaluated through biomechanical skin property measurements and cytotoxicity in HaCaT and RAW 267 cells. Leishmanicidal activity was tested against promastigotes and amastigotes of Leishmania infantum, and in silico studies were conducted to explore possible mechanisms of action. The composition of the MA-gel included 30% MA, 20% Pluronic^® F127 (P407), and 50% water. Scanning electron microscopy revealed a sponge-like and porous internal structure of the MA-gel. This formula exhibited a pH of 5.45, swelling at approximately 12 min, and a porosity of 85.07%. The DSC showed that there was no incompatibility between MA and P407. Drug release followed a first-order kinetic profile, with 22.11 µg/g/cm² of the drug retained in the skin and no permeation into the receptor compartment. The MA-gel showed no microbial growth, no cytotoxicity in keratinocytes, and no skin damage. The IC₅₀ for promastigotes and amastigotes of L. infantum were 3.56 and 23.11 µg/mL, respectively. In silico studies suggested that MA could act on three potential therapeutic targets according to its binding mode. The MA-gel demonstrated promising physicochemical, safety, and antiparasitic properties, supporting its potential as a topical treatment for cutaneous leishmaniasis. Full article

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

The pharmaceutical industry faces significant challenges when promising drug candidates fail during development due to suboptimal ADME (absorption, distribution, metabolism, excretion) properties or toxicity concerns. Natural compounds are subject to the same pharmacokinetic considerations. In silico approaches offer a compelling advantage—they eliminate the need for physical samples and laboratory facilities, while providing rapid and cost-effective alternatives to expensive and time-consuming experimental testing. Computational methods can often effectively address common challenges associated with natural compounds, such as chemical instability and poor solubility. Through a review of the relevant scientific literature, we present a comprehensive analysis of in silico methods and tools used for ADME prediction, specifically examining their application to natural compounds. Whereas we focus on identifying the predominant computational approaches applicable to natural compounds, these tools were developed for conventional drug discovery and are of general use. We examine an array of computational approaches for evaluating natural compounds, including fundamental methods like quantum mechanics calculations, molecular docking, and pharmacophore modeling, as well as more complex techniques such as QSAR analysis, molecular dynamics simulations, and PBPK modeling. Full article

Background/Objectives: In the last few decades, the dengue virus, a prevalent flavivirus, has demonstrated various epidemiological, economic, and health impacts around the world. Dengue virus serotype 2 (DENV2) plays a vital role in dengue-associated mortality. The RNA-dependent RNA polymerase (RdRp) of DENV2 is a charming druggable target owing to its crucial function in viral reproduction. In recent years, streptomycetes natural products (NPs) have attracted considerable attention as a potential source of antiviral drugs. Methods: Seeking prospective inhibitors that inhibit the DENV2 RdRp allosteric site, in silico mining of the Streptome database was executed. AutoDock4.2.6 software performance in predicting docking poses of the inspected inhibitors was initially conducted according to existing experimental data. Upon the assessed docking parameters, the Streptome database was virtually screened against DENV2 RdRp allosteric site. The streptomycetes NPs with docking scores less than the positive control (68T; calc. −35.6 kJ.mol⁻¹) were advanced for molecular dynamics simulations (MDS), and their binding affinities were computed by employing the MM/GBSA approach. Results: SDB9818 and SDB4806 unveiled superior inhibitor activities against DENV2 RdRp upon MM/GBSA//300 ns MDS than 68T with ΔG_binding values of −246.4, −242.3, and −150.6 kJ.mol⁻¹, respectively. A great consistency was found in both the energetic and structural analyses of the identified inhibitors within the DENV2 RdRp allosteric site. Furthermore, the physicochemical characteristics of the identified inhibitors demonstrated good oral bioavailability. Eventually, quantum mechanical computations were carried out to evaluate the chemical reactivity of the identified inhibitors. Conclusions: As determined by in silico computations, the identified streptomycetes NPs may act as DENV2 RdRp allosteric inhibitors and mandate further experimental assays. Full article

Estrogen receptor alpha (ERα) plays a vital role in the development and progression of breast cancer by regulating the expression of genes associated with cell proliferation in breast tissue. ERα inhibition is a key strategy in the prevention and treatment of breast cancer. Previous research modified chalcone compounds into pyrazoline benzenesulfonamide derivatives (Modifina) which show activity as an ERα inhibitor. This study aimed to design novel pyrazoline benzenesulfonamide derivatives (PBDs) as ERα antagonists using in silico approaches. Structure-based and ligand-based drug design approaches were used to create drug target molecules. A total of forty-five target molecules were initially designed and screened for drug likeness (Lipinski’s rule of five), cytotoxicity, pharmacokinetics and toxicity using a web-based prediction tools. Promising candidates were subjected to molecular docking using AutoDock 4.2.6 to evaluate their binding interaction with ERα, followed by molecular dynamics simulations using AMBER20 to assess complex stability. A pharmacophore model was also generated using LigandScout 4.4.3 Advanced. The molecular docking results identified PBD-17 and PBD-20 as the most promising compounds, with binding free energies (ΔG) of −11.21 kcal/mol and −11.15 kcal/mol, respectively. Both formed hydrogen bonds with key ERα residues ARG394, GLU353, and LEU387. MM-PBSA further supported these findings, with binding energies of −58.23 kJ/mol for PDB-17 and −139.46 kJ/mol for PDB-20, compared to −145.31 kJ/mol, for the reference compound, 4-OHT. Although slightly less favorable than 4-OHT, PBD-20 demonstrated a more stable interaction with ERα than PBD-17. Furthermore, pharmacophore screening showed that both PBD-17 and PBD-20 aligned well with the generated model, each achieving a match score of 45.20. These findings suggest that PBD-17 and PBD-20 are promising lead compounds for the development of a potent ERα inhibitor in breast cancer therapy. Full article

Accurate in vitro models of intestinal permeability are essential for predicting oral drug absorption. Standard models like Caco-2 cells have well-known limitations, including lack of segment-specific physiology, but are widely used. Emerging models such as organoid-derived monolayers and microphysiological systems (MPS) offer enhanced physiological relevance but require comparative validation. We performed a head-to-head evaluation of Caco-2 cells, human jejunal (J2) and duodenal (D109) enteroid-derived cells, and EpiIntestinal^TM tissues cultured on either static Transwell and flow-based MPS platforms. We assessed tissue morphology, barrier function (TEER, dextran leakage), and permeability of three model small molecules (caffeine, propranolol, and indomethacin), integrating the data into a physiologically based gut absorption model (PECAT) to predict human oral bioavailability. J2 and D109 cells demonstrated more physiologically relevant morphology and higher TEER than Caco-2 cells, while the EpiIntestinal^TM model exhibited thicker and more uneven tissue structures with lower TEER and higher passive permeability. MPS cultures offered modest improvements in epithelial architecture but introduced greater variability, especially with enteroid-derived cells. Predictions of human fraction absorbed (F_abs) were most accurate when using static Caco-2 data with segment-specific corrections based on enteroid-derived values, highlighting the utility of combining traditional and advanced in vitro gut models to optimize predictive performance for F_abs. While MPS and enteroid-based systems provide physiological advantages, standard static models remain robust and predictive when used with in silico modeling. Our findings support the need for further refinement of enteroid-MPS integration and advocate for standardized benchmarking across gut model systems to improve translational relevance in drug development and regulatory reviews. Full article

Background/Objectives: Banhasasim-tang (BHSST) is a traditional herbal formula commonly used to treat gastrointestinal (GI) disorders and has been considered a potential therapeutic option for irritable bowel syndrome (IBS). This study aimed to explore the molecular targets and underlying mechanisms of BHSST in IBS using a combination of network pharmacology, molecular docking, molecular dynamics simulations, and in vivo validation. Methods: Active compounds in BHSST were screened based on drug-likeness and oral bioavailability. Potential targets were predicted using ChEMBL, and IBS-related targets were obtained from GeneCards and DisGeNET. A compound–target–disease network was constructed and analyzed via Gene Ontology and KEGG pathway enrichment. Compound–target interactions were further assessed using molecular docking and molecular dynamics simulations. The in vivo effects of eudesm-4(14)-en-11-ol, elemol, and BHSST were evaluated in a zymosan-induced IBS mouse model. Results: Twelve BHSST-related targets were associated with IBS, with enrichment analysis identifying TNF signaling and apoptosis as key pathways. In silico simulations suggested stable binding of eudesm-4(14)-en-11-ol to TNF-α and kanzonol T to PIK3CD, whereas elemol showed weak interaction with PRKCD. In vivo, eudesm-4(14)-en-11-ol improved colon length, weight, stool consistency, TNF-α levels, and pain-related behaviors—effects comparable to those of BHSST. Elemol, however, showed no therapeutic benefit. Conclusions: These findings provide preliminary mechanistic insight into the anti-inflammatory potential of BHSST in IBS. The integrated in silico and in vivo approaches support the contribution of specific components, such as eudesm-4(14)-en-11-ol, to its observed effects, warranting further investigation. Full article

Resistance of various bacterial pathogens to the activity of clinically approved drugs currently leads to serious infections, rapid spread of difficult-to-treat diseases, and even death. Taking the threats for human health in mind, researchers are focused on the isolation and characterization of novel natural products, including plant secondary metabolites. These molecules serve as inspiration and a suitable structural platform in the design and development of novel semi-synthetic and synthetic derivatives. All considered compounds have to be adequately evaluated in silico, in vitro, and in vivo using relevant approaches. The current review paper briefly focuses on the chemical and metabolic properties of resveratrol (1), as well as its oligomeric structures, viniferins, and viniferin-based molecules. The core scaffolds of these compounds contain so-called privileged structures, which are also present in many clinically approved drugs, indicating that those natural, properly substituted semi-synthetic, and synthetic molecules can provide a notably broad spectrum of beneficial pharmacological activities, including very impressive antimicrobial efficiency. Except for spectral verification of their structures, these compounds suffer from the determination or prediction of other structural and physicochemical characteristics. Therefore, the structure–activity relationships for specific dihydrodimeric and dimeric viniferins, their bioisosteres, and derivatives with notable efficacy in vitro, especially against chosen Gram-positive bacterial strains, are summarized. In addition, a set of descriptors related to their structural, physicochemical, pharmacokinetic, and toxicological properties is generated using various computational tools. The obtained values are compared to those of clinically approved drugs. The particular relationships between these in silico parameters are also explored. Full article

The present study investigated the neuroprotective potential of the Murraya carbazole derivatives murrayanol, mahanimbine, murrayafoline A, and 9-methyl-9H-carbazole-2-carbaldehyde using in silico and in vitro assays. The pharmacokinetic properties and potential toxicity (ADME/T) of the carbazole derivatives were assessed to evaluate their prospects as up-and-coming drug candidates. Molecular docking was used to investigate the interactions of the compounds with Aβ (PDB: 1IYT, 2BEG, and 8EZE) and AChE receptors (PDB: 4EY7 and 1C2B). The results from the in vitro assays were used to validate and support the findings from the in silico assays. The compounds demonstrated significant inhibition of acetylcholinesterase (AChE), a key target in neurodegenerative disorders. Murrayanol and mahanimbine presented superior inhibitory activity (IC₅₀ ~0.2 μg/mL), outperforming the reference drug, galantamine. The inhibition mechanisms were competitive (murrayanol, murrayafoline A, and 9-methyl-9H-carbazole-2-carbaldehyde) and non-competitive (mahanimbine), supported by low Ki values and strong docking affinities. The compounds also proved effective in reducing Aβ fibrillization (murrayanol: 40.83 ± 0.30%; murrayafoline A: 33.60 ± 0.55%, mahanimbine: 27.68 ± 2.71%). These findings highlight Murraya carbazoles as promising scaffolds for multifunctional agents in AD therapy. Further optimization and mechanistic studies are warranted to advance their development into clinically relevant neuroprotective agents. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

The scientific community’s interest in natural compounds with antiviral properties has considerably increased after the emergence of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), especially for their potential use in the treatment of the COVID-19 infection. From this perspective, bovine coronavirus (BCoV), member of the genus β-CoV, represents a valuable virus model to study human β-CoVs, bypassing the risks of handling highly pathogenic and contagious viruses. Pimarane diterpenes are a significant group of secondary metabolites produced by phytopathogenic fungi, including several Diplodia species. Among the members of this class of natural products, sphaeropsidin A (SphA) and its analog sphaeropsidin B (SphB) are well known for their bioactivities, such as antimicrobial, insecticidal, herbicidal, and anticancer. In this study, the antiviral effects of SphA and SphB were evaluated for the first time on bovine (MDBK) cells infected with BCoV. Our findings showed that both sphaeropsidins significantly increased cell viability in infected cells. These substances also caused substantial declines in the virus yield and in the levels of the viral spike S protein. Interestingly, during the treatment, a cellular defense mechanism was detected in the downregulation of the aryl hydrocarbon receptor (AhR) signaling, which is affected by BCoV infection. We also observed that the presence of SphA and SphB determined the deacidification of the lysosomal environment in infected cells, which may be related to their antiviral activities. In addition, in silico investigations have been performed to elucidate the molecular mechanism governing the recognition of bovine AhR (bAhR) by Sphs. Molecular docking studies revealed significant insights into the structural determinants driving the bAhR binding by the examined compounds. Hence, in vitro and in silico results demonstrated that SphA and SphB are promising drug candidates for the development of efficient therapies able to fight a β-CoV-like BCoV during infection. Full article

EGFR is the most frequently altered driver gene in non-small-cell lung cancer (NSCLC), and its overexpression is also associated with breast cancer. In the present study, we synthesized 18 new compounds (B-1, B-2, B-6, B-7, and BP-1–14). The cytotoxicity of these compounds was evaluated in A549 NSCLC and MCF-7 breast cancer cells, as well as in Jurkat cells and PBMCs (healthy). The most potent compounds were further examined for their ability to induce apoptosis in A549 and MCF-7 cells, as well as their EGFR inhibitory activity. Molecular docking was conducted at the ATP-binding site of EGFR, and key pharmacokinetic and toxicity parameters were predicted in silico. B-2 demonstrated the strongest cytotoxicity against A549 and MCF-7 cells (IC₅₀ = 2.14 ± 0.83 μM and 8.91 ± 1.38 μM, respectively), displaying selective cytotoxicity between Jurkat cells and PBMCs (SI = 23.2). B-2 induced apoptosis in A549 and MCF-7 cells at rates of 16.8% and 4.3%, respectively. B-2 inhibited EGFR by 66% at a 10 μM concentration and showed a strong binding affinity to the ATP-binding site of EGFR. Furthermore, B-2 exhibited drug-like characteristics and was not identified as carcinogenic, genotoxic, or mutagenic. B-2 shows promise as an apoptosis inducer and EGFR inhibitor for future anti-NSCLC and anti-breast cancer research. Full article