Search Results (301)

Ulcerative colitis (UC) is a chronic inflammatory condition that affects the intestines. Research has shown that reducing the activity of DDR1 can help maintain intestinal barrier function in UC, making DDR1 a promising target for treatment. However, the development of DDR1 inhibitors as drugs has been hindered by issues such as toxicity and poor binding stability. As a result, there are currently no DDR1-targeting drugs available for clinical use, highlighting the need for new inhibitors. In a recent study, a dataset of 85 DDR1 inhibitors was analyzed to identify key characteristics for effective inhibition. A pharmacophore model was constructed and validated to screen a library of marine natural products for potential DDR1 inhibitors. Through high-throughput virtual screening and precise docking, 17 promising compounds were identified from a pool of over 52,000 molecules in the marine database. To improve binding affinity and reduce potential toxicity, scaffold hopping was employed to modify the 17 compounds, resulting in the generation of 1070 new compounds. These new compounds were further evaluated through docking and ADMET analysis, leading to the identification of three compounds—39713a, 34346a, and 34419a—with superior predicted activity and drug-like properties compared to the original 17 compounds. Further analysis showed that the binding free energy values of the three candidate compounds were less than −12.200 kcal/mol, which was similar to or better than −12.377 kcal/mol of the known positive compound VU6015929, and the drug-like properties were better than those of the positive compounds. Molecular dynamics simulations were then conducted on these three candidate compounds, confirming their stable interactions with the target protein. In conclusion, compounds 39713a, 34346a, and 34419a show promise as potential DDR1 inhibitors for the treatment of ulcerative colitis. Full article

Background/Objectives: Antimicrobial resistance and oxidative stress are major global health challenges, necessitating the development of novel therapeutic agents. Pyrazole derivatives, known for their diverse pharmacological properties, hold promise in addressing these issues. This study aimed to synthesize new mono- and bis-pyrazole derivatives using an eco-friendly, catalyst-free approach and evaluate their antioxidant, antibacterial, and antifungal activities, supported by in silico ADMET profiling, molecular docking, and Density Functional Theory (DFT) analysis. Methods: The compounds were synthesized via a green condensation reaction and characterized using NMR and mass spectrometry, which was verified by DFT analysis. Biological activities were assessed through DPPH and FRAP antioxidant assays, as well as disk diffusion and MIC methods, against bacterial strains (Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli) and fungal strains (Candida albicans and Aspergillus niger). Computational ADMET profiling evaluated pharmacokinetics and toxicity, while molecular docking assessed interactions with target proteins, including catalase, topoisomerase IV, and CYP51. Results: Theoretical calculations using DFT were in agreement with the experimental results; regarding biological activities, O4 demonstrated the most significant antioxidant activity, with 80.14% DPPH radical scavenging and an IC50 value of 40.91 µg/mL. It exhibited potent antimicrobial activity, surpassing Streptomycin with a 30 mm inhibition zone against Pseudomonas aeruginosa and showing strong efficacy against Staphylococcus aureus and Candida albicans. Computational studies confirmed favorable pharmacokinetic properties, no AMES toxicity, and strong binding affinities. DFT analysis revealed O4’s stability and reactivity, further validating its potential as a therapeutic candidate. Conclusions: This study identified and characterized novel pyrazole derivatives with promising biological and pharmacological properties. O4 emerged as the most potent compound, demonstrating strong antioxidant and antimicrobial activities alongside favorable computational profiles. These findings highlight the potential of the synthetized compounds for therapeutic development and underscore the value of integrating green synthesis with computational techniques in drug discovery. Full article

Background: Schizophrenia manifests through behavioral abnormalities, suicidal ideation, and neuropsychological deficits. Hence, this study focused on 5-hydroxytryptamine (5-HT 2C) which influenced the modulation of the series of events that lead to schizophrenia. Methodology: Based on the computational study, the potential 5-HT 2C inhibitors such as Ephemeranthoquinone from Arundina graminifolia and Actinodaphnine from Litsea polyantha were determined. The candidate ligands were optimized using the Gaussian 16 software package and the DFT 6-31g (d,p) basis set. The interaction between the ligands and proteins was examined with PyRx 0.8. Additionally, pharmacokinetics was assessed using SwissADME, and Protox II for toxicity prediction. The network pharmacology study was examined by using the STRING database and the Cytoscape 3.10.1 tool. Moreover, a 100-nanosecond molecular dynamics simulation analysis using Desmond to ensure the stability of these two compounds was carried out. Result: This computational research observed that ephemeranthoquinone and actinodaphnine are the most selective 5-HT 2C inhibitors due to their docking score, optimization, and molecular dynamics simulation results. Conclusions: These compounds are required to be studied further to develop a useful 5-HT 2C inhibitors for the treatment of schizophrenia. Full article

Tribulus terrestris is a rich source of bioactive molecules and thrives in Mediterranean and desert climate regions worldwide. In this study, Tribulus terrestris methanolic HPLC fractions were evaluated for bioactive compounds and PBP2a transpeptidase inhibitors against methicillin-resistant Staphylococcus epidermidis (MRSE). Among the collected HPLC fractions, F02 of the methanol extract demonstrated potential activity against MRSE01 (15 ± 0.13 mm), MRSE02 (13 ± 0.21 mm), and MRSE03 (16 ± 0.14 mm) isolates. GC-MS analysis of the F02 fraction identified seventeen compounds. Among seventeen compounds, eight have favorable pharmacokinetics and medicinal chemistry; however, on the basis of in silico high water solubility, high GI absorption, blood–brain barrier non-permeability, lack of toxicity, and potential drug-likeness, 1-ethylsulfanylmethyl-2,8,9-trioxa-5-aza-1-sila-bicyclo[3.3.3]undecane and phthalimide, N-(1-hydroxy-2-propyl), were processed for molecular docking. 1-ethylsulfanylmethyl-2,8,9-trioxa-5-aza-1-sila-bicyclo[3.3.3]undecane formed three hydrogen bonds with Ser-452, Thr-584, and Asn-454 residues of the PBP2a transpeptidase. Similarly, phthalimide, N-(1-hydroxy-2-propyl)-formed four hydrogen bonds with Ser-396, Asn-454, Lys-399, and Ser-452 residues of PBP2a transpeptidase. These two compounds are proposed as novel putative PBP2a transpeptidase inhibitors. Further characterization of compounds extracted from Tribulus terrestris may aid in identifying novel PBP2a inhibitory agents for managing MRSE infections. Full article

Considering our previous experience in the design of new cholinesterase inhibitors, especially resveratrol analogs, in this research, the basic stilbene skeleton was used as a structural unit for new carbamates designed as potentially highly selective butyrylcholinesterase (BChE) inhibitors with excellent absorption, distribution, metabolism, excretion and toxicity ADMET properties. The inhibitory activity of newly prepared carbamates 1–13 was tested toward the enzymes acetylcholinesterase (AChE) and BChE. In the tested group of compounds, the leading inhibitors were 1 and 7, which achieved excellent selective inhibitory activity for BChE with IC₅₀ values of 0.12 ± 0.09 μM and 0.38 ± 0.01 μM, respectively. Both were much more active than the standard inhibitor galantamine against BChE. Molecular docking of the most promising inhibitor candidates, compounds 1 and 7, revealed that stabilizing interactions between the active site residues of BChE and the ligands involve π-stacking, alkyl-π interactions, and, when the carbamate orientation allows, H-bond formation. MD analysis confirmed the stability of the obtained complexes. Some bioactive resveratrol-based carbamates displayed complex-forming capabilities with Fe³⁺ ions as metal centers. Spectrophotometric investigation indicated that they coordinate one or two metal ions, which is in accordance with their chemical structure, offering two binding sites: an amine and a carboxylic group in the carbamate moiety. Based on the obtained in silico, experimental and computational results on biological activity in the present work, new carbamates 1 and 7 represent potential selective BChE inhibitors as new therapeutics for neurological disorders. Full article

Background/Objectives: Kynurenine aminotransferase II (KAT-II) is a target for treating several diseases characterized by an excess of kynurenic acid (KYNA). Although KAT-II inactivators are available, they often lead to adverse side effects due to their irreversible inhibition mechanism. This study aimed to identify potent and safe inhibitors of KAT-II using computational and in vitro approaches. Methods: Virtual screening, MM/GBSA, and molecular dynamics simulations were conducted to identify the top drug candidates, followed by kinetic measurements and in vitro cytotoxicity evaluation. Results: The study showed that two compounds, herbacetin and (-)-Epicatechin exhibited the best scores. Their Glide docking scores are −8.66 kcal/mol and −8.16 kcal/mol, respectively, and their MM/GBSA binding energies are −50.30 kcal/mol and −51.35 kcal/mol, respectively. These scores are superior to those of the standard inhibitor, PF-04859989, which has docking scores of −7.12 kcal/mol and binding energy of −38.41 kcal/mol. ADMET analysis revealed that the selected compounds have favorable pharmacokinetic parameters, moderate bioavailability, and a safe toxicity profile, which supports their potential use. Further, the kinetic study showed that herbacetin and (-)-Epicatechin are reversible KAT-II inhibitors and exhibit a competitive inhibition mechanism. Their half-maximal inhibitory concentrations (IC50) are 5.98 ± 0.18 µM and 8.76 ± 0.76 µM, respectively. The MTT assay for cell toxicity indicated that the two compounds do not affect HepG2 cell viability at the necessary concentration for KAT-II inhibition. Conclusions: These results suggest that herbacetin and (-)-Epicatechin are suitable for KAT-II inhibition and are promising candidates for further development of KAT-II inhibitors. Full article

LCN2, a member of the lipocalin family, is associated with various tumors and inflammatory conditions. Despite the availability of known inhibitors, none have been approved for clinical use. In this study, marine compounds were screened for their ability to inhibit LCN2 using pharmacophore models. Six compounds were optimized for protein binding after being docked against the positive control Compound A. Two compounds showed promising results in ADMET screening. Molecular dynamics simulations were utilized to predict binding mechanisms, with Compound 69081_50 identified as a potential LCN2 inhibitor. MM-PBSA analysis revealed key amino acid residues that are involved in interactions, suggesting that Compound 69081_50 could be a candidate for drug development. Full article

Background/Objectives: Silybum marianum extract, obtained via microwave-enhanced extraction, was evaluated for its antioxidant, antidiabetic, and antimicrobial activities to explore its therapeutic potential. Methods: The extraction was performed using microwave-enhanced techniques, and LC-MS/MS was employed to profile the metabolites in the extract. Total phenolic and flavonoid contents were quantified using spectrophotometric methods. Antioxidant activity was assessed using DPPH, ABTS, CUPRAC, Phenanthroline, and FRAP assays. Enzyme inhibition assays were conducted to evaluate antidiabetic activity against α-glucosidase and α-amylase. Antimicrobial activity was determined using the disc diffusion method, and in silico ADMET and drug-likeness analyses were performed for key metabolites. Results: The extract contained 251.2 ± 1.2 mg GAE/g of total phenolics and 125.1 ± 1.6 mg QE/g of total flavonoids, with 33 metabolites identified, including phenolic acids, tannins, flavonoids, and flavolignans. Strong antioxidant activity was observed, with IC₅₀ values of 19.2 ± 2.3 μg/mL (DPPH), 7.2 ± 1.7 μg/mL (ABTS), 22.2 ± 1.2 μg/mL (CUPRAC), 35.2 ± 1.8 μg/mL (Phenanthroline), and 24.1 ± 1.2 μg/mL (FRAP). Antidiabetic effects were significant, with IC₅₀ values of 18.1 ± 1.7 μg/mL (α-glucosidase) and 26.5 ± 1.3 μg/mL (α-amylase). Antimicrobial activity demonstrated inhibition zones of 8.9 ± 1.1 mm (Bacillus subtilis), 12.6 ± 1.6 mm (Escherichia coli), 8.2 ± 1.2 mm (Fusarium oxysporum), and 9.2 ± 1.1 mm (Aspergillus niger). In silico analyses showed high absorption, favorable metabolism and excretion, and minimal toxicity, with no hERG channel inhibition or hepatotoxicity. Conclusions: The comprehensive results highlight the significant antioxidant, antidiabetic, and antimicrobial activities of S. marianum extract, suggesting its potential for therapeutic and preventive applications. Full article

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. Methods: This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation. The database, obtained from the Coconut website, was filtered according to a set of physicochemical descriptors, then was shape screened against the crystal ligand conformation. This filtered database consisting of 26,325 compounds was used for virtual screening against the GLP-1 allosteric site. Results: The results identified ten best hits with the XP score ranging from −9.6 to −7.6 and MM-GBSA scores ranging from −50.8 to −32.4 and another 58 hits from docked pose filter and a second round of XP docking and MM-GBSA calculation followed by molecular dynamics. The analysis of results identified hits from various natural products (NPs) classes, to whom attributed antidiabetic and anti-obesity effects have been previously reported. The results also pointed to β-lactam antibiotics that may be evaluated in drug repurposing studies for off-target effects. The calculated ADMET properties for those hits revealed suitable profiles for further development in terms of bioavailability and toxicity. Conclusions: The current study identified several NPs as potential GLP-1 positive allosteric modulators and revealed common structural scaffolds including peptidomimetics, lactams, coumarins, and sulfonamides with peptidomimetics being the most prominent especially in indole and coumarin cores. Full article

The arid mountainous region of Hail in Saudi Arabia has a variety of desert vegetation, some of which are conventionally used in Bedouin traditional medicine. These plants need scientific examination. This research seeks to examine Blepharis ciliaris using a thorough multi-analytical methodology that includes antibacterial and antioxidant assessments as well as computational modeling. GC–MS analysis of the methanolic extract revealed 17 organic compounds, including pentadecanoic acid, ethyl methyl ester (2.63%); hexadecanoic acid, methyl ester (1.00%); 9,12-octadecadienoic acid (Z,Z)-, methyl ester (2.74%); 9-octadecenoic acid, methyl ester (E) (2.78%); octadecanoic acid (5.88%); 9-tetradecenoic acid (Z) (3.22%); and undec-10-enoic acid, undec-2-n-1-yl ester (5.67%). The DPPH test evaluated antioxidant activity, revealing a notable increase with higher concentrations of the methanolic extract, achieving maximum inhibition of 81.54% at 1000 µg/mL. The methanolic extract exhibited moderate antibacterial activity, with average inhibition zones of 10.33 ± 1.53 mm, 13.33 ± 1.53 mm, 10.67 ± 1.53 mm, and 10.00 ± 2.00 mm against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Serratia marcescens, respectively, as determined by the disk diffusion method. The minimum inhibitory concentration (MIC) values were 500 µg/mL for S. aureus and B. subtilis, whereas E. coli and S. marcescens showed susceptibility at 1000 µg/mL. Computational simulations were employed to assess the toxicity, drug-likeness, and ADMET profiles of compounds derived from Blepharis ciliaris. Thirteen bioactive compounds were assessed in silico against Staphylococcus aureus sortase A (PDB: 1T2O), Bacillus subtilis BsFabHb (PDB: 8VDB), Escherichia coli LPS assembly protein (LptD) (PDB: 4RHB), and a modeled Serratia marcescens outer-membrane protein TolC, focusing on cell wall and membrane structures. Compound 3, (+)-Ascorbic acid 2,6-dihexadecanoate, shown significant binding affinities to B. subtilis BsFabHb, E. coli LPS assembly protein, and S. marcescens TolC. Full article

This investigation aimed to assess the in vitro and in silico biological properties of the ethyl acetate (EtOAc) extract obtained from leaves of Rubus ulmifolius Schott collected in Algeria. The phytochemical screening data disclosed that flavonoids, tannins, coumarins, saponins, and anthocyanins were abundant. High levels of total phenolics, total flavonoids and flavonols (523.25 ± 3.53 µg GAE/mg, 20.41 ± 1.80, and 9.62 ± 0.51 µg QE/mg respectively) were detected. Furthermore, GC-MS analysis was performed to identify low molecular weight compounds. d-(-)-Fructofuranose, gallic acid, caffeic acid, and catechin were detected as main metabolites of the EtOAc extract. The outcomes revealed that the extract exerted a potent antioxidant apt, and ensured significant bacterial growth inhibitory capacity, where the inhibition zone diameters ranged from 20.0 ± 0.5 to 24.5 ± 0.3 mm. These outcomes were confirmed through molecular docking against key bacterial enzymes that revealed significant interactions and binding affinities. d-(-)-Fructofuranose was identified as the most polar and flexible compound. Gallic acid and caffeic acid demonstrated higher unsaturation. Caffeic acid was well absorbed in the blood–brain barrier (BBB) and human intestine. Catechin was well absorbed in CaCO₃, and can act as an inhibitor of CYP1A2. These results highlight how crucial it is to keep looking into natural substances in the quest for more potent and targeted pathology therapies. Full article

Alkylphenols are byproducts of anthropogenic activities that widely contaminate waters, soils and air; among them, the most represented are 4-nonylphenol (4-NP) and 4-octylphenol (4-OP). These compounds tend to bioaccumulate in animal and plant tissues and also represent a risk to human health. Indeed, humans are constantly exposed to alkylphenols through ingestion of contaminated water and food, inhalation and dermal absorption. In the present work, we characterized the cytotoxic ability of 4-OP towards several human cell lines, representing the potential main targets in the human body, also comparing its effect with that of 4-NP and of a mixture of both 4-OP and 4-NP in a range of concentrations between 1 and 100 μM. Viability assays demonstrated that each cell type had a peculiar sensitivity to 4-OP and that, in some cases, a combination of the two alkylphenols displayed a higher cytotoxic activity with respect to the single compound. Then, we focused our attention on a liver cell line (HepG2) in which we observed that 4-OP increased cell death and also caused interference with protective physiological cell processes, such as the unfolded protein response, autophagy and the antioxidant response. Finally, our experimental data were compared and correlated with ADMET properties originating from an in silico analysis. Altogether, our findings highlight a possible contribution of this pollutant to deregulation of the normal homeostasis in human liver cells. Full article

Background/Objectives: Spatholobi Caulis (SPC) is a medicinal plant that mainly grows in China and Southeast Asian countries and commonly used in clinics; the pharmacokinetic characteristics in humans need to be determined. This study was to establish the physiologically based pharmacokinetic (PBPK) models of multiple active constituents from SPC in rats, and predict the pharmacokinetic properties of rats with different dosages and extrapolated to humans. Methods: The parameters were collected based on our previous study and by prediction using ADMET Predictor software predict. The PBPK models for 3′-methoxydadizein (1), 8-O-methylretusin (2), daidzin (3), and isolariciresinol (4) administered orally to rats were established using GastroPlus software. These models were employed to simulate the pharmacokinetic properties in rats across various dosages, and subsequently extrapolated to humans. The calculated parameters including C_max, T_max, and AUC were compared with observed values. The accuracy of the PBPK models was assessed using fold-error (FE) values. Result: The FE values ranged from 1.03 to 1.52, meeting the PBPK model regulations where FE should be less than 2. The sensitivity analysis focusing on the absorption amount and AUC_0→t of these four constituents in humans was also conducted. These results confirm the successful establishment of PBPK models of these four constituents from SPC in this study, and these models were applicable to predict pharmacokinetics across various doses and extrapolate across species. Conclusions: The PBPK models of four constituents can be used to predict the pharmacokinetic characteristics in humans after oral administration of SPC and provide useful data for safe and rational medication in clinical practice. Full article

Dovyalis abyssinica is widely used in Ethiopia for treating various human ailments, yet its pharmacological properties and chemical composition remain largely unexplored. The chromatographic separation of D. abyssinica roots extract afforded five compounds, namely tremulacin (1), cochinchiside A (2), 5-methoxydurmillone (3), catechin-7-O-α-L-rhamnopyranoside (4), and stigmasterol (5), confirmed via IR, NMR, and MS spectral data. This is the first report of these compounds from this plant, except for compounds 1 and 5. The extracts and isolated compounds were tested for antibacterial activity against S. aureus, S. epidermidis, E. faecalis, E. coli, K. pneumoniae, and P. aeruginosa strains. Methanol roots extract exhibited significant antibacterial activity (MIC 0.195 mg/mL) against E. coli and P. aeruginosa. Compounds 1 and 3 showed remarkable antibacterial activity, with compound 1 (MIC 0.625 mg/mL) exhibiting antibacterial activity against S. aureus and S. epidermidis, whereas compound 3 (MIC 0.625 mg/mL) exhibited antibacterial activity against S. epidermidis and K. pneumoniae. Molecular docking analysis revealed better binding energies for compound 1 (−8.0, −9.7, and −8.0 kJ/mol) and compound 3 (−9.0, −8.7, and −8.4 kJ/mol), compared to ciprofloxacin (−8.3, −7.5, and −6.7 kJ/mol), in regard to S. aureus pyruvate kinase, S. epidermidis FtsZ, and K. pneumoniae Topoisomerase IV, respectively. ADME analysis also revealed good antibacterial candidacy of these compounds, provided that in vivo analysis is conducted for further confirmation of the results. Full article

A novel series of substituted benzofuran-tethered triazolylcarbazoles was synthesized in good to high yields (65–89%) via S-alkylation of benzofuran-based triazoles with 2-bromo-N-(9-ethyl-9H-carbazol-3-yl)acetamide. The inhibitory potency of the synthesized compounds against SARS-CoV-2 was evaluated by enacting molecular docking against its three pivotal proteins, namely, M^pro (main protease; PDB ID: 6LU7), the spike glycoprotein (PDB ID: 6WPT), and RdRp (RNA-dependent RNA polymerase; PDB ID: 6M71). The docking results indicated strong binding affinities between SARS-CoV-2 proteins and the synthesized compounds, which were thereby expected to obstruct the function of SARS proteins. Among the synthesized derivatives, the compounds 9e, 9h, 9i, and 9j exposited the best binding scores of −8.77, −8.76, −8.87, and −8.85 Kcal/mol against M^pro, respectively, −6.69, −6.54, −6.44, and −6.56 Kcal/mol against the spike glycoprotein, respectively, and −7.61, −8.10, −8.01, and −7.54 Kcal/mol against RdRp, respectively. Furthermore, the binding scores of 9b (−8.83 Kcal/mol) and 9c (−8.92 Kcal/mol) against 6LU7 are worth mentioning. Regarding the spike glycoprotein, 9b, 9d, and 9f expressed high binding energies of −6.43, −6.38, and −6.41 Kcal/mol, accordingly. Correspondingly, the binding affinity of 9g (−7.62 Kcal/mol) against RdRp is also noteworthy. Furthermore, the potent compounds were also subjected to ADMET analysis to evaluate their pharmacokinetic properties, suggesting that the compounds 9e, 9h, 9i, and 9j exhibited comparable values. These potent compounds may be selected as inhibitory agents and provide a pertinent context for further investigations. Full article