Search Results (40)

The rise in multidrug-resistant bacteria highlights the critical need for novel antibiotics. This study explores clovibactin-like compounds as potential therapeutic agents targeting lipid II, a crucial component in bacterial cell wall synthesis, using in silico techniques. A total of 2624 clovibactin analogs were sourced from the PubChem database and screened using ProTox 3.0 software based on their ADME-Tox properties, prioritizing candidates with favorable pharmacokinetic profiles and minimal toxicity. Molecular docking protocols were then employed to assess the binding interactions of the selected compounds with lipid II. Our analysis identified Compound 22 as a particularly promising candidate, exhibiting strong binding affinity, stable complex formation, and high selectivity for the target. Binding energy analysis, conducted via molecular dynamics simulations, revealed a highly negative value of −25.50 kcal/mol for Compound 22, surpassing that of clovibactin and underscoring its potential efficacy. In addition, Compound 22 was prioritized due to its exceptional binding affinity to lipid II and its favorable ADME-Tox properties, suggesting a lower likelihood of adverse effects. These characteristics position Compound 22 as a promising candidate for further pharmacological development. While our computational results are encouraging, experimental validation is essential to confirm the efficacy and safety of these compounds. This study not only advances our understanding of clovibactin analogs but also contributes to the ongoing efforts to combat antimicrobial resistance through innovative antibiotic development. Full article

Origanum majorana L., also known as sweet marjoram, is a plant with multiple uses, both in the culinary field and traditional medicine, because of its major antioxidant, anti-inflammatory, antimicrobial, and digestive properties. In this research, we focused on the effects of O. majorana essential oil (OmEO, at concentrations of 25, 150, and 300 μL/L), evaluating chemical structure as well as its impact on cognitive performance and oxidative stress, in both naive zebrafish (Danio rerio), as well as in a scopolamine-induced amnesic model (SCOP, 100 μM). The fish behavior was analyzed in a novel tank-diving test (NTT), a Y-maze test, and a novel object recognition (NOR) test. We also investigated acetylcholinesterase (AChE) activity and the brain’s oxidative stress status. In parallel, we performed in silico predictions (research conducted using computational models) of the pharmacokinetic properties of the main compounds identified in OmEO, using platforms such as SwissADME, pKCSM, ADMETlab 2.0, and ProTox-II. The results revealed that the major compounds were trans-sabinene hydrate (36.11%), terpinen-4-ol (17.97%), linalyl acetate (9.18%), caryophyllene oxide (8.25%), and α-terpineol (6.17%). OmEO can enhance memory through AChE inhibition, reduce SCOP-induced anxiety by increasing the time spent in the top zone in the NTT, and significantly reduce oxidative stress markers. These findings underscore the potential of using O. majorana to improve memory impairment and reduce oxidative stress associated with cognitive disorders, including Alzheimer’s disease (AD). Full article

Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs commonly used worldwide for their analgesic and antipyretic effects. However, an overdose of NSAIDs can have negative effects on various systems, including the cardiovascular, gastrointestinal, hepatic, renal, and neural systems. The search for new, safer, and more effective anti-inflammatory agents has now become a necessity. The aim of the present study is to identify new natural compounds that act against cyclooxygenase-2 (COX-2), one of the main anti-inflammatory targets, using computational approaches. For this purpose, molecular docking and MM/GBSA binding free energy calculations were utilized to discover new natural inhibitors for COX-2. In addition, several prediction tools, such as SwissADME server, QikProp, and Pro-Tox II, were used in this study to elucidate the pharmacokinetic properties, drug-likeness ability, safety, and the lethal dose (LD₅₀) of the studied compounds. The results of molecular docking have indicated that among all phytochemicals under examination, canniprene, oroxylin A and luteolin show high docking scores and binding affinities toward COX-2 (−10.587, −10.254, and −9.494 Kcal.mol⁻¹, respectively) when compared with the reference inhibitor. Moreover, the top hits demonstrated stability during molecular dynamics simulation and were found to conform to drug-like rules with good bioavailability. Toxicity parameters of the best hits indicate that these compounds could be safe COX-2 inhibitors, but further in vitro and in vivo studies are needed to confirm these findings. Full article

There is a growing interest in the discovery of novel xanthine oxidase inhibitors for gout prevention and treatment with fewer side effects. This study aimed to identify the xanthine oxidase (XO) inhibitory potential and drug-likeness of the metabolites present in the methanolic leaf extract of Anastatica (A.) hierochuntica L. using in vitro and in silico models. The extract-derived metabolites were identified by liquid-chromatography–quadrupole-time-of-flight-mass-spectrometry (LC-QTOF-MS). Molecular docking predicted the XO inhibitory activity of the identified metabolites and validated the best scored in vitro XO inhibitory activities for experimental verification, as well as predictions of their anticancer, pharmacokinetic, and toxic properties; oral bioavailability; and endocrine disruption using SwissADMET, PASS, ProTox-II, and Endocrine Disruptome web servers. A total of 12 metabolites, with a majority of flavonoids, were identified. Rutin, quercetin, and luteolin flavonoids demonstrated the highest ranked docking scores of −12.39, −11.15, and −10.43, respectively, while the half-maximal inhibitory concentration (IC₅₀) values of these metabolites against XO activity were 11.35 µM, 11.1 µM, and 21.58 µM, respectively. In addition, SwissADMET generated data related to the physicochemical properties and drug-likeness of the metabolites. Similarly, the PASS, ProTox-II, and Endocrine Disruptome prediction models stated the safe and potential use of these natural compounds. However, in vivo studies are necessary to support the development of the prominent and promising therapeutic use of A. hierochuntica methanolic-leaf-extract-derived metabolites as XO inhibitors for the prevention and treatment of hyperuricemic and gout patients. Furthermore, the predicted findings of the present study open a new paradigm for these extract-derived metabolites by revealing novel oncogenic targets for the potential treatment of human malignancies. Full article

Terpenoids constitute one of the most widespread phytoconstituents, with complex chemical structures, a plurality of biological activities, and variable pharmacokinetic profiles. The emerging roles of terpenoids in drug design require an understanding of their ADME/T properties for structure modification and possible repurposing. This study evaluated the drug-likeness of phytotoxic terpenoids obtained from the Toxic Plants–Phytotoxins (TPPT) database via in silico prediction of their pharmacokinetic and toxicity profiles. The TPPT database, comprising 1586 phytotoxins, was filtered to 576 terpenoids. Using Swiss ADME, pkCSM, and ProTox II webserver tools, Lipinski’s properties and topological polar surface area (TPSA) were predicted for drug-likeness, alongside their pharmacokinetic profiles and toxicity on various organ endpoints. In total, 9.55% of the terpenoids obeyed Lipinski’s rule of five. None of the compounds inhibited hERG I, while 12.73% inhibited hERG II, implying that some were cardiotoxic. In addition, 25.45% of the compounds elicited AMES toxicity; 25.45% caused liver injury; and 32.73% caused skin sensitivity. Furthermore, 72.73% showed high Caco-2 permeability and 76.36% displayed good skin permeability, implying their suitability for transdermal drug delivery. P-glycoprotein was extruded by 29.09% of the compounds and inhibited by 34.45%; 47.27% of the compounds readily crossed the blood–brain barrier, 23.64% penetrated the central nervous system, 56.36% were sensitive to cytochrome p450 isoenzymes, 36.37% inhibited cytochrome p450 isoenzymes, 49.09% resulted in immunotoxicity, 1.82% were toxic to cells, 14.55% would cause cancer, and 21.82% showed high tolerated doses in humans. Most of them showed a high volume of distribution, were free-flowing in plasma, and demonstrated moderate bioavailability, while all had high intestinal absorption and 78.18% demonstrated good water solubility. This study identified marrubiin as a drug-like, non-toxic, and highly bioavailable terpenoid with strong potential for further optimization, and development. Full article

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. Methods: First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Results: Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Conclusions: Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management. Full article

Medicinal plants have been utilized since ancient times for their therapeutic properties, offering potential solutions for various ailments, including epidemics. Among these, Leptadenia reticulata, a member of the Asclepiadaceae family, has been traditionally employed to address numerous conditions such as diarrhea, cancer, and fever. In this study, employing HR-LCMS/MS(Q-TOF) analysis, we identified 113 compounds from the methanolic extract of L. reticulata. Utilizing Lipinski’s rule of five, we evaluated the drug-likeness of these compounds using SwissADME and ProTox II. SwissTarget Prediction facilitated the identification of potential inflammatory targets, and these targets were discerned through the Genecard, TTD, and CTD databases. A network pharmacology analysis unveiled hub proteins including CCR2, ICAM1, KIT, MPO, NOS2, and STAT3. Molecular docking studies identified various constituents of L. reticulata, exhibiting high binding affinity scores. Further investigations involving in vivo testing and genomic analyses of metabolite-encoding genes will be pivotal in developing efficacious natural-source drugs. Additionally, the potential of molecular dynamics simulations warrants exploration, offering insights into the dynamic behavior of protein–compound interactions and guiding the design of novel therapeutics. Full article

Background and Objectives: Cyclooxygenase-2 (COX-2) is mostly linked to inflammation and has been validated as a molecular target for treating inflammatory diseases. The present study aimed to identify novel compounds that could inhibit COX-2, which is associated with various diseases including inflammation, and in such a scenario, plant-derived biomolecules have been considered as attractive candidates. Materials and Methods: In the present study, physiochemical properties and toxicity of natural compounds/drugs were determined by SWISSADME and ProTox-II. In the present study, the molecular docking binding features of saffron derivatives (crocetin, picrocrocin, quercetin, safranal, crocin, rutin, and dimethylcrocetin) against human COX-2 protein were assessed. Moreover, protein-protein interactions, topographic properties, gene enrichment analysis and molecular dynamics simulation were also determined. Results: The present study revealed that picrocrocin showed the highest binding affinity of −8.1 kcal/mol when docked against the COX-2 protein. PROCHECK analysis revealed that 90.3% of the protein residues were found in the most favored region. Compartmentalized Protein–Protein Interaction identified 90 interactions with an average interaction score of 0.62, and the highest localization score of 0.99 found in secretory pathways. The Computed Atlas of Surface Topography of Proteins was used to identify binding pockets and important residues that could serve as drug targets. Use of WEBnmα revealed protein dynamics by using normal mode analysis. Ligand and Receptor Dynamics used the Molecular Generalized Born Surface Area approach to determine the binding free energy of the protein. Gene enrichment analysis revealed that ovarian steroidogenesis, was the most significant enrichment pathway. Molecular dynamic simulations were executed for the best docked (COX-2-picrocrocin) complex, and the results displayed conformational alterations with more pronounced surface residue fluctuations in COX-2 with loss of the intra-protein hydrogen bonding network. The direct interaction of picrocrocin with various crucial amino-acid residues like GLN²⁰³, TYR³⁸⁵, HIS^{386 and 388}, ASN³⁸², and TRP³⁸⁷ causes modifications in these residues, which ultimately attenuates the activity of COX-2 protein. Conclusions: The present study revealed that picrocrocin was the most effective biomolecule and could be repurposed via computational approaches. However, various in vivo and in vitro observations are still needed. Full article

Parkinson’s disease is an idiopathic neurodegenerative disorder which is characterized by the degeneration of the neurons of substantia nigra, a part of the midbrain, regulating motor movement. It involves a decrease in the levels of dopamine which consequently hampers movement control. In the literature, natural compounds like flavonoids have been cited to exhibit their potential to terminate the augmentation of such a disorder by penetrating the blood–brain barrier. In this study, 10 phytoconstituents were screened using molecular docking against the dopamine D3 receptor to identify potential inhibitors. The PDB database was employed to extract the target protein of interest, i.e., the dopamine D3 receptor (PDB ID: 3PBL). Both the test drugs and the standard moiety were obtained in their 3D conformation from the PubChem in SDF format, while FlexX software was used for docking purposes. The docking scores of the selected photochemical were hence compared with Levodopa, which was taken as the positive control. The docking studies revealed that Vasicol has the closest docking score (−19.6871 kcal/mol) to that of the standard Levodopa (−23.1188 kcal/mol), proving that it has the best molecular docking result for the dopamine D3 receptor. Also, the low toxicity profile confirmed by the pro Tox-II online server indicated that Vasicol is a potential lead to be a drug candidate for treating Parkinson’s disease. Full article

Parkinson’s disease is a neurodegenerative disease which involves the malfunction and death of vital nerve cells in the brain, called neurons, which produce dopamine. Dopamine is a neurotransmitter that communicates with the area of the brain responsible for movement and coordination. As Parkinson’s disease progresses, the amount of dopamine production in the brain declines, leaving a person unable to control movement. Typically, natural compounds such as flavanoids have been cited in the literature for having the ability to penetrate the blood–brain barrier and halt the progression of such disorders. In this study, ten phytoconstituents were screened using molecular docking against adenosine A2A to identify potential inhibitors. Target protein of interest, Adenosine A2A receptor (PDB ID: 3UZA) was extracted from PDB database. Test drugs as well as standard drug were extracted in their 3D conformation from the PubChem in .SDF format, and docking was done using FlexX software. The docking scores of the selected photochemical were compared with levodopa as a positive control. Docking studies revealed that Baicaline has best molecular docking result (−21.6 kcal/mol) for Adenosine A2A receptor, with low toxicity as per pro Tox-II online server which indicates that the Baicalein is a potential lead to be drug candidate for Parkinson’s disease. Full article

In the search for new potential drug candidates acting as anticancer agents, we were interested in a small molecule derived from 4-hydroxy-2-quinolone, which is newly synthesized from the condensation of a β-enaminone and diethylmalonate under microwave irradiation. This compound was subjected to an in silico study in order to investigate its potentiality to act against lung cancer through inhibiting a tyrosine kinase: Anaplastic Lymphoma Kinase (ALK). A docking simulation was performed in the active pocket of the human ALK complexed with a commercialized anticancer agent—Entrectinib (Pdb: 5FTO)—using Schrodinger suite. The studied derivative showed good stability inside the active site with an estimated docking score equal to −8.054 kcal·mol⁻¹. In addition, significant interactions, similar to those formed by the co-crystallized ligand, were present in the studied compound, counting hydrogen bonds with Met1199 and Glu1197 as well as hydrophobic contacts with residues in the cavity of the ALK. Keeping in mind that the pharmacokinetic properties and the toxicity of a drug candidate are very important factors in conceiving a safe admissible therapeutic substance, we carried out an ADMET prediction for the studied molecules using SwissADME, MolSoft, and ProTox-II, which gave promising results. Full article

Juncus acutus, acknowledged through its indigenous nomenclature “samar”, is part of the Juncaceae taxonomic lineage, bearing considerable import as a botanical reservoir harboring conceivable therapeutic attributes. Its historical precedence in traditional curative methodologies for the alleviation of infections and inflammatory conditions is notable. In the purview of Eastern traditional medicine, Juncus species seeds find application for their remedial efficacy in addressing diarrhea, while the botanical fruits are subjected to infusion processes targeting the attenuation of symptoms associated with cold manifestations. The primary objective of this study was to unravel the phytochemical composition of distinct constituents within J. acutus, specifically leaves (JALE) and roots (JARE), originating from the indigenous expanse of the Nador region in northeastern Morocco. The extraction of plant constituents was executed utilizing an ethanol-based extraction protocol. The subsequent elucidation of chemical constituents embedded within the extracts was accomplished employing analytical techniques based on high-performance liquid chromatography (HPLC). For the purpose of in vitro antioxidant evaluation, a dual approach was adopted, encompassing the radical scavenging technique employing 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the total antioxidant capacity (TAC) assay. The acquired empirical data showcase substantial radical scavenging efficacy and pronounced relative antioxidant activity. Specifically, the DPPH and TAC methods yielded values of 483.45 ± 4.07 µg/mL and 54.59 ± 2.44 µg of ascorbic acid (AA)/mL, respectively, for the leaf extracts. Correspondingly, the root extracts demonstrated values of 297.03 ± 43.3 µg/mL and 65.615 ± 0.54 µg of AA/mL for the DPPH and TAC methods. In the realm of antimicrobial evaluation, the assessment of effects was undertaken through the agar well diffusion technique. The minimum inhibitory concentration, minimum bactericidal concentration, and minimum fungicidal concentration were determined for each extract. The inhibitory influence of the ethanol extracts was observed across bacterial strains including Staphylococcus aureus, Micrococcus luteus, and Pseudomonas aeruginosa, with the notable exception of Escherichia coli. However, fungal strains such as Candida glabrata and Rhodotorula glutinis exhibited comparatively lower resistance, whereas Aspergillus niger and Penicillium digitatum exhibited heightened resistance, evincing negligible antifungal activity. An anticipatory computational assessment of pharmacokinetic parameters was conducted, complemented by the application of the Pro-tox II web tool to delineate the potential toxicity profile of compounds intrinsic to the studied extracts. The culmination of these endeavors underpins the conceivable prospects of the investigated extracts as promising candidates for oral medicinal applications. Full article

V-agents are exceedingly toxic nerve agents. Recently, it was highlighted that V-agents constitute a diverse subclass of compounds with most of them not extensively studied. Although chemical weapons have been banned under the Chemical Weapons Convention (CWC), there is an increased concern for chemical terrorism. Thus, it is important to understand their properties and toxicities, especially since some of these agents are not included in the CWC list. Nonetheless, to achieve this goal, the testing of a huge number of compounds is needed. Alternatively, in silico toxicology offers a great advantage for the rapid assessment of toxic compounds. Here, various in silico tools (TEST, VEGA, pkCSM ProTox-II) were used to estimate the acute oral toxicity (LD50) of different V-agents and compare them with experimental values. These programs underestimated the toxicity of V-agents, and certain V-agents were estimated to be relatively non-toxic. TEST was also used to estimate the physical properties and found to provide good approximations for densities, surface tensions and vapor pressures but not for viscosities. Thus, attention should be paid when interpreting and estimating the toxicities of V-agents in silico, and it is necessary to conduct future detailed experiments to understand their properties and develop effective countermeasures. Full article

In the current study, we described the synthesis of ten new 5-(3-Bromophenyl)-N-aryl-4H-1,2,4-triazol-3-amine analogs (4a–j), as well as their characterization, anticancer activity, molecular docking studies, ADME, and toxicity prediction. The title compounds (4a–j) were prepared in three steps, starting from substituted anilines in a satisfactory yield, followed by their characterization via spectroscopic techniques. The National Cancer Institute (NCI US) protocol was followed to test the compounds’ (4a–j) anticancer activity against nine panels of 58 cancer cell lines at a concentration of 10⁻⁵ M, and growth percent (GP) as well as percent growth inhibition (PGI) were calculated. Some of the compounds demonstrated significant anticancer activity against a few cancer cell lines. The CNS cancer cell line SNB-75, which showed a PGI of 41.25 percent, was discovered to be the most sensitive cancer cell line to the tested compound 4e. The mean GP of compound 4i was found to be the most promising among the series of compounds. The five cancer cell lines that were found to be the most susceptible to compound 4i were SNB-75, UO-31, CCRF-CEM, EKVX, and OVCAR-5; these five cell lines showed PGIs of 38.94, 30.14, 26.92, 26.61, and 23.12 percent, respectively, at 10⁻⁵ M. The inhibition of tubulin is one of the primary molecular targets of many anticancer agents; hence, the compounds (4a–j) were further subjected to molecular docking studies looking at the tubulin–combretastatin A-4 binding site (PDB ID: 5LYJ) of tubulin. The binding affinities were found to be efficient, ranging from −6.502 to −8.341 kcal/mol, with two major electrostatic interactions observed: H-bond and halogen bond. Ligand 4i had a binding affinity of −8.149 kcal/mol with the tubulin–combretastatin A-4 binding site and displayed a H-bond interaction with the residue Asn258. The ADME and toxicity prediction studies for each compound were carried out using SwissADME and ProTox-II software. None of the compounds’ ADME predictions showed that they violated Lipinski’s rule of five. All of the compounds were also predicted to have LD₅₀ values between 440 and 500 mg/kg, putting them all in class IV toxicity, according to the toxicity prediction. The current discovery could potentially open up the opportunity for further developments in cancer. Full article

This study examines the impact of irrigation water quality on the synthesis of secondary metabolites and the chemical composition of Mentha piperita essential oil (MPEO). Three essential oils from Mentha piperita plants, irrigated with different water sources commonly used for mint irrigation in Morocco’s Oriental region, were analyzed. The water sources were characterized based on various parameters, such as nitrites, nitrates, orthophosphates, chemical oxygen demand (COD), biological oxygen demand (BOD5), pH, and electrical conductivity. The essential oils were extracted using hydrodistillation, and their chemical composition was determined using gas chromatography coupled with mass spectrometry (GC/MS), revealing notable variations among the compositions of the three essential oils. In this study, in silico tests using the Prediction of Activity Spectra for Substances (PASS) algorithm; the absorption, distribution, metabolism, and excretion (ADME) model; and Pro-Tox II were conducted to evaluate the drug-likeness, pharmacokinetic properties, expected safety profile upon ingestion, and potential pharmacological activity of the identified compounds in MPEO. The antioxidant activity of the MPEOs was assessed through a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and the total antioxidant activity (TAC) method. Additionally, the antimicrobial effectiveness of the essential oils was tested against four bacterial strains (Staphylococcus aureus, Micrococcus luteus, Escherichia coli, Pseudomonas aeruginosa) and four fungal strains (Candida glabrata, Rhodotorula glutinis, Penicillium digitatum, Aspergillus niger), demonstrating moderate to strong activities against the tested strains. This study concludes that regulating irrigation water quality can enhance the production of specific metabolites, making them potentially valuable as antioxidants and antimicrobial agents. Full article