Search Results (202)

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that requires therapeutic agents capable of targeting multiple pathological pathways. In this study, a series of cannabidiol (CBD)-like hydrazone derivatives (3a–i) was synthesized and characterized by NMR, HRMS, and single-crystal X-ray diffraction for compound 3i. In silico ADME analysis predicted favorable drug-like properties, including compliance with Lipinski’s Rule of Five, oral bioavailability, and blood–brain barrier permeability. The compounds were evaluated for cholinesterase inhibition, antioxidant activity, cytotoxicity in neuronal cell lines, and binding interactions with human butyrylcholinesterase (hBChE) by molecular docking. Biological evaluation revealed a marked preference for BChE over acetylcholinesterase (AChE). Compound 3f was the most potent BChE inhibitor (IC₅₀ = 1.67 ± 0.11 μM), while compounds 3b and 3f demonstrated high selectivity toward BChE. Antioxidant assays (DPPH, ABTS, FRAP, and FTC) indicated moderate, mechanism-dependent activity. Compounds 3b and 3e showed the strongest ABTS radical-scavenging effects, whereas compounds 3b and 3f provided the greatest protection against lipid peroxidation, surpassing CBD under the tested conditions. Several derivatives, particularly 3a, 3b, 3f, 3h, and 3i, exhibited favorable safety profiles in SH-SY5Y and Neuro-2a cells. Molecular docking supported the experimental findings. Overall, compounds 3b and 3f emerged as promising multifunctional leads for the development of multitarget-directed anti-Alzheimer agents. Full article

The demand for sustainable nutrients and bioactive compounds has increased interest in underutilized wild plants. Forestiera tomentosa, a Mexican drupe-bearing species, is largely unexplored. This study evaluated the proximate composition, physicochemical and functional properties, phenolic profile, antioxidant capacity, and toxicological safety of F. tomentosa fruit. The fruit showed high carbohydrate content [71.94% dry weight (DW)], with notable crude fiber (7.90% DW), protein (7.39% DW), and lipid (4.30% DW) contents. Analysis revealed a mildly acidic pH (5.66), titratable acidity of 0.32%, and total soluble solids of 2.33 °Brix. The fruit powder had a low water activity (0.42) and a favorable water solubility index (56.10%), oil absorption (4.54%), and foaming capacity (19.71%). The fruit contained high levels of soluble phenols (280.42 mg GAE/g DW), flavonoids (98.89 mg CE/g DW), anthocyanins (54.53 mg C3G/g DW), and condensed tannins (94.05 mg CE/g DW). High-performance liquid chromatography identified 20 phenolic compounds, with 3-(4-hydroxyphenyl) propionic acid, syringic acid, catechin, epicatechin, and gallocatechin being predominant. The fruit showed significant radical scavenging and reducing potential (DPPH, ABTS, and FRAP). Toxicological evaluation using the Artemia salina bioassay showed a 100% survival rate across all concentrations, indicating no acute toxicity. In silico ADMET predictions revealed favorable pharmacokinetic properties, including high intestinal absorption and compliance with Lipinski’s rule of five. These findings position F. tomentosa as a promising, non-toxic source of functional ingredients for the food, nutraceutical, and pharmaceutical industries, supporting biodiversity conservation and sustainable resource utilization. Further studies are needed to evaluate the potential health benefits of this fruit in vitro and in vivo. Full article

The development of multi-targeted therapeutic agents is increasingly recognized as essential for treating multifactorial diseases. Butyrolactone I and butyrolactone III, γ-butyrolactone derivatives isolated from the marine fungus Aspergillus terreus, represent structurally related natural products with largely unexplored polypharmacological potential. This study employed a comprehensive in silico approach combining ADMET profiling, quantum chemical calculations, molecular docking, and molecular dynamics simulations to evaluate their therapeutic potential across multiple pharmacological targets. Physicochemical analysis revealed favorable drug-like properties for both compounds, with complete compliance with Lipinski’s Rule of Five, high predicted gastrointestinal absorption (>80%), and acceptable toxicity profiles (toxicity class 4, LD₅₀ = 2000 mg/kg). Neither compound showed hepatotoxic, neurotoxic, cardiotoxic, carcinogenic, or mutagenic liabilities. Frontier molecular orbital analysis (DFT/B3LYP/6-31G(d,p)) revealed comparable HOMO energies (−6.054 and −6.059 eV), with butyrolactone III exhibiting enhanced kinetic stability based on a larger HOMO–LUMO gap (4.662 eV vs. 4.443 eV) and higher chemical hardness (η = 2.331 eV vs. 2.222 eV). Molecular docking against four therapeutic targets revealed target-selective binding profiles: butyrolactone III demonstrated binding affinity toward acetylcholinesterase exceeding donepezil (−9.0 vs. −8.3 kcal/mol), while butyrolactone I exhibited MDM2 binding affinity slightly exceeding nutlin-3a (−7.8 kcal/mol). Both compounds showed moderate interactions with COX-2 and topoisomerase IV. Molecular dynamics simulations validated the stability of AChE complexes (RMSD < 2.0 Å) and the MDM2–butyrolactone I complex (RMSD: 0.69 ± 0.09 Å), while the MDM2–butyrolactone III complex exhibited significant instability (RMSD up to 3.55 Å), highlighting the critical role of the prenyl group in MDM2 recognition. These findings, consistent with, though not a direct experimental validation of, previously published in vitro data, support the evaluation of butyrolactone III as a scaffold for neuroprotective agents and butyrolactone I as a p53 pathway modulator for cancer therapy, illustrating the potential value of fungal metabolites in multi-target drug discovery and the role of integrated computational approaches in prioritizing candidates for subsequent experimental testing. Full article

With the introduction of Navarixin in clinical trials, the role of squaric acid derivatives as bioisosteres gained popularity. Because of their distinctive electronic properties and hydrogen-bonding capacity, these compounds hold considerable promise for medicinal chemistry applications. In this study, a series of novel furan- and thiophene-containing squaric acid derivatives was synthesized via base-catalyzed nucleophilic substitution and characterized by spectroscopic techniques. The structures of three compounds were additionally confirmed by X-ray crystallography. Density functional theory calculations showed good agreement with the experimental vibrational spectra. In silico evaluation predicted favorable drug-like characteristics, including compliance with Lipinski’s rule of five and high gastrointestinal absorption. The cytotoxic activity of the synthesized compounds was assessed against HeLa, HT-29, HL-60, A-549, and MCF-7 cancer cell lines, as well as the non-cancerous CCL-1 cell line. Several derivatives displayed moderate to strong antiproliferative activity with selectivity toward malignant cells. Compound 3d exhibited the most pronounced improvement (five-fold) over Navarixin in HL-60 cells 5.81 µM, while compounds 3a and 3c demonstrated superior potency and selectivity in A-549 cells (10.33 µM and 9.65 µM). These findings identify squaric acid derivatives as promising candidates for further anticancer drug development and structure–activity relationship studies. Full article

Background: Cyclin-dependent kinase 2 (CDK2) is a key regulator of cell cycle progression and an important therapeutic target in cancer treatment. This study aims to identify novel CDK2 inhibitors using an integrated computational approach combining machine learning and structure-based methods. Methods: A computational pipeline was developed incorporating Lipinski’s Rule of Five filtering, machine learning (ML)-based activity prediction, molecular docking, and molecular dynamics simulations (MDs). A dataset of CDK2 inhibitors with IC50 values was retrieved from ChEMBL, and molecular fingerprints were generated using PaDEL. A 5-fold stratified cross-validation approach was applied to train multiple classifiers, with the random forest model showing the best performance. Predicted active compounds from the InterBioScreen database were subjected to docking against CDK2 (PDB ID: 2FVD) using PyRx, followed by 100 ns MDS for stability analysis. Results: The random forest classifier achieved an AUC-ROC of 0.90 and an accuracy of 0.84. A total of 187 compounds were predicted as active. Among these, two compounds, STOCK4S-00019 and STOCK4S-00025, demonstrated docking scores comparable to the co-crystallized reference ligand. Molecular dynamics simulations confirmed stable binding, consistent interaction patterns, and favorable conformational behavior throughout the simulation period. Conclusions: The identified compounds, STOCK4S-00019 (hit1) and STOCK4S-00025 (hit2), show strong potential as CDK2 inhibitors. These findings support their further investigation through experimental validation and highlight the effectiveness of integrated computational approaches in anticancer drug discovery. Full article

This study aims identify plant-derived compounds that can inhibit glutathione peroxidase 4 (GPX4) enzyme and evaluate them through molecular docking, dynamics simulations, and ADMET analyses. The 3D structure of the GPX4 protein (PDB ID: 2OBI) was obtained from the Protein Data Bank. The plant-derived ligand library was compiled from the PubChem database and screened for compliance with Lipinski’s rules using ADMETLAB 2.0. Molecular docking simulations were performed using Autodock Vina. Molecular dynamics simulations of 100 nanoseconds were performed for the selected ligand–protein complexes using AMBER Tools and OpenMM software. The ADMET properties of the ligands were evaluated using the pKCSM web server. Compared to the reference inhibitor RSL3 (−7.2 kcal/mol), five plant compounds showed stronger binding affinity: withaferin A (−8.0 kcal/mol), mahanine (−7.9 kcal/mol), pseudobufarenogin (−7.8 kcal/mol), cucurbitacin I (−7.6 kcal/mol), and liquiritin (−7.5 kcal/mol). Molecular dynamics simulations showed that the complexes of withaferin A, mahanine, and liquiritin exhibited superior structural stability. ADMET analysis revealed that the compounds generally possess acceptable pharmacokinetic profiles but require some bioavailability optimization. The identified plant-derived compounds can be considered as potential therapeutic agents in cancer treatment by inducing ferroptosis via GPX4 inhibition. These findings provide an important basis for natural product-derived drug discovery studies. Full article

The increasing prevalence of multidrug-resistant Staphylococcus aureus (MRSA) has necessitated the development of alternative therapeutic strategies targeting bacterial virulence factors. This study employed an integrated in silico approach to identifying potential inhibitors of the iron-regulated surface determinant B Near-iron Transporter domain, a key protein involved in heme acquisition and pathogenicity. Virtual screening and molecular docking identified certain similarity-selected small molecules possessing strong binding affinities, with (4-(1-oxoisoindolin-2-yl)benzoic acid (TOP1) and (4-(2-oxochromen-3-yl)benzoic acid (TOP2) exhibiting the most favorable binding energies at −12.0 and −11.8 kcal/mol, respectively. Molecular dynamics simulations over 200 ns confirmed stable protein–ligand interactions that yielded reduced structural fluctuations in ligand-bound complexes when compared with the apo form. Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) analysis revealed that van der Waals interactions were the primary contributors to binding, with TOP1 showing a more favorable overall binding energy. Drug-likeness and pharmacokinetic predictions indicated compliance with Lipinski’s rule of five and moderate bioavailability, although limited intestinal absorption was observed. Toxicity predictions indicated that both compounds are non-mutagenic but may exhibit hepatotoxicity. Notably, TOP1 exhibited potential nephrotoxicity, cardiotoxicity, and carcinogenicity, whereas TOP2 demonstrated a more favorable safety profile. These findings highlight a trade-off between binding affinity and safety, suggesting that TOP2 emerged as a computationally prioritized candidate for future experimental validation. Because the present findings represent computational predictions only, further orthogonal computational analyses and experimental studies are required to confirm the proposed binding modes, biological activity, and therapeutic potential of the identified compounds. Full article

The aim of the present study was to evaluate the bioavailability and associated bioactivity of p-coumaric (p-COA), caffeic (CA), and ferulic (FA) hydroxycinnamic acids (HCAs) isolated from an aqueous extract of plant material. An aqueous extract is more applicable in practice because this form is the most commonly used for oral administration. The p-COA, CA, and FA acids were evaluated for their behavior in the processes of absorption, distribution, metabolism, and excretion (ADME) using modern methods for assessing their functional groups according to Lipinski’s Rule of Five and the Rule of Nines. Given the available data on extensive metabolism of hydroxycinnamic acids during the first pass through the liver, it is necessary to consider an alternative route of administration, namely the sublingual route. Sublingual delivery of exogenous molecules obtained from plant material by extraction may represent a preferable alternative to oral administration, as first-pass hepatic metabolism is bypassed when dosage forms are administered sublingually. Full article

This study investigates the phytochemical and pharmacological profiles of Crinum asiaticum L. var. anomalum Baker from Vietnam. Phytochemical screening identified diverse secondary metabolites, including polyphenols, flavonoids, and alkaloids. Gas chromatography–mass spectrometry analysis of the n-hexane fractions revealed 19 major compounds. While all extracts showed moderate antioxidant activity, the chloroform fraction exhibited superior antidiabetic potential via α-amylase inhibition (IC₅₀ = 83.13 ± 6.67 µg/mL). Furthermore, at non-cytotoxic concentrations (3.13 to 50 µg/mL), this fraction effectively rescued mouse β-TC6 insulinoma cells from thapsigargin. In anti-inflammatory assays, the n-hexane fraction significantly suppressed nitric oxide production in RAW 264.7 macrophages (IC₅₀ = 53.12 ± 1.63 µg/mL). Notably, the extracts displayed remarkable selective anticancer activity, particularly the chloroform fraction against HeLa cervical and HepG2/Huh-7 hepatoma cell lines. In silico ADMET and Lipinski’s Rule of Five analyses confirmed that the key bioactive constituents possess favorable pharmacokinetic profiles and drug-likeness. These findings demonstrate C. asiaticum L. var. anomalum Baker as a promising natural source for developing multitarget therapeutic agents against inflammation, diabetes, and cancer. Full article

Parkinson’s disease is strongly linked to lysosomal dysfunction, particularly reduced activity of glucocerebrosidase (GCase) encoded by the GBA1 gene. Stabilizing GCase using small-molecule modulators represents a promising therapeutic strategy. In this study, phytochemicals from Xylia xylocarpa (Roxb.) Taub., a medicinal plant with reported neuroprotective potential, were profiled using LC-QTOF-MS and evaluated as GCase stabilizers through an integrated computational approach. LC-MS analysis in positive and negative modes tentatively identified 19 metabolites, of which 13 low-molecular-weight compounds (<500 Da) were selected for molecular docking against human GCase. Docking revealed six compounds with higher predicted binding affinity than the reference activator Pyrrolopyrazine. Pharmacokinetic screening based on Lipinski’s rule of five and ADMET predictions identified Senbusine A as a viable lead candidate. It exhibited favorable binding interactions, forming stabilizing contacts within a non-catalytic inter-monomer interface associated with structural modulation of GCase. PASS analysis suggested a high probability of neuroactive properties. Molecular dynamics simulations (200 ns) confirmed stable binding and reduced conformational fluctuations compared to apo and control systems. Overall, computational predictions identify Senbusine A as a potential pharmacological chaperone-like stabilizer of GCase, exhibiting a favorable pharmacological profile and warranting further experimental validation. Full article

The rising threat of antimicrobial resistance necessitates the search for novel bioactive molecules from natural sources. This study investigated the phytochemical composition, antibacterial potency, and molecular docking interactions of Citrus aurantium peel ethanol extract against Escherichia coli outer-membrane and topoisomerase proteins and Staphylococcus aureus toxins as drug target proteins. Qualitative and quantitative phytochemical compositions were examined using standard analytical methods, chemical compounds were evaluated and qualified using Gas Chromatography–Mass Spectrometry (GC-MS), and antibacterial effects were investigated in silico and validated in vitro. Qualitative and quantitative analyses revealed high concentrations of flavonoids (4.54 ± 0.11%), alkaloids (1.6 ± 0.03%), terpenoids (1.35 ± 0.01%), tannins (1.02 ± 0.05%), phenols (0.97 ± 0.07%), and saponins (0.80 ± 0.01%). GC–MS profiling identified several dominant compounds, including β-D-glucopyranose, neo-inositol, 8-(2,3-dihydroxy-3-methylbutyl)-7-methoxy-2H-chromen-2-one, and D-allose. In silico docking studies against bacterial druggable proteins (PDB IDs: 4C56 and 3MFG, which are S. aureus toxins; 1BXW and 3FV5, which are E. coli outer-membrane and topoisomerase proteins) revealed strong binding affinities (−6.477 to −8.774 kcal/mol), comparable to standard antibiotics. ADMET predictions confirmed favorable pharmacokinetic and safety profiles, with most lead compounds displaying high intestinal absorption, low hepatotoxicity, and compliance with Lipinski’s rule of five. The extract exhibited stronger antibacterial activity, producing inhibition zones of 25.11 ± 0.017 and 23.04 ± 0.25 mm against clinical isolates of S. aureus and E. coli, respectively, at a concentration of 10 mg/mL, comparable to ciprofloxacin (30.35 ± 0.26 mm). These findings highlight C. aurantium peel phytoconstituents as promising scaffolds for antibacterial drug development and justify further in vivo validation for combating multidrug-resistant pathogens. Full article

Reaction of 5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carbohydrazide with selected aldehydes and ketone provided novel hydrazone derivatives bearing azole moieties: pyrazole, pyrrole, and indole. The drug likeness of the newly synthesized compounds and their physicochemical characteristics were examined to fit Lipinski’s Rule of Five. N-(2,5-dimethyl-1H-pyrrol-1-yl)-5-oxo-1-(4-(phenylamino)phenyl)pyrrolidine-3-carboxamide (5) exhibited the most favorable overall ADMET profile, combining compliance with key physicochemical requirements for antimicrobial activity with superior solubility and reduced predicted hepatotoxicity and nephrotoxicity. Despite generally elevated plasma protein binding across the series, this compound provided the most advantageous balance between permeability, systemic exposure, and safety. Full article

Objectives: Visceral leishmaniasis (VL), caused by Leishmania donovani and Leishmania infantum, is a life-threatening neglected tropical disease, particularly in endemic regions such as Djibouti. Current therapies are constrained by toxicity, high cost, and limited availability, highlighting the urgent need for safe, effective, and affordable alternatives. This study aimed to identify novel antileishmanial candidates from Djiboutian medicinal plants using an integrated in silico approach. Methods: A total of 136 phytoconstituents isolated from local medicinal plants were screened via molecular docking against validated protein targets (6UAK and 2JK6). Promising candidates were further analyzed for interaction patterns, drug-likeness according to Lipinski’s Rule of Five, and ADMET properties. Molecular dynamics (MD) simulations over 100 ns were performed to assess the structural stability of selected protein–ligand complexes. Results: Compound C41 emerged as a leading candidate, showing binding affinities of −8.3 kcal/mol and −7.5 kcal/mol toward 6UAK and 2JK6, respectively, comparable to reference drugs. Interaction analysis revealed stable hydrogen bonds and hydrophobic contacts within the catalytic sites. Drug-likeness assessment confirmed compliance with Lipinski’s Rule, while ADMET predictions indicated high intestinal absorption and favorable safety profiles for several candidates. MD simulations corroborated the structural stability of the 2JK6-C41 complex throughout the 100 ns trajectory. Conclusions: These findings underscore Djiboutian medicinal plants as a valuable source of potential antileishmanial leads. Among them, Compound C41 represents a promising candidate for future experimental validation, supporting the development of innovative, safe, and cost-effective therapies against visceral leishmaniasis. Full article

Background: The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, remains a significant threat to global health. This continued threat is due to the emergence of new variants, the immune system’s limited ability to respond, and the limited effectiveness of available treatments for all individuals. Therefore, leveraging drug repurposing, a fast and inexpensive way to find other drugs that have already been shown to be safe and efficacious, becomes useful. This study leverages ADMET profiling, network pharmacology, and molecular docking to evaluate the repurposing of Product Nkabinde for COVID-19 treatment. Methods: ADMET analysis involving the bioactive phytochemicals of PN was evaluated for pharmacokinetic appropriateness and drug-likeness. Using topological analysis, a network of protein–protein interactions was built to identify hub genes, and predicted compound targets were intersected with COVID-19-associated genes to find shared targets. Their biological importance was characterized using functional enrichment analysis. The binding affinities of PN phytochemicals against hub proteins and SARS-CoV-2 viral proteases (Mpro and PLpro) were assessed by molecular docking using AutoDock Vina. To confirm docking accuracy, co-crystallized ligands were redocked using Schrodinger 2022-1. The multi-target therapeutic potential of PN in COVID-19 was assessed using this integrative network pharmacology and molecular docking technique. Results: Molecular docking demonstrated that PN phytochemicals displayed robust and persistent binding affinities for both viral and host targets. Oleanolic acid showed the best affinity toward Mpro (−12.9 kcal/mol vs. −8.3 kcal/mol), while quercetin-3-O-β-D-(6′-galloyl)-glucopyranoside showed better binding to PLpro (−8.4 kcal/mol vs. −6.4 kcal/mol). Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol), diosgenin toward EGFR (−9.4 vs. −8.4 kcal/mol), rutin toward SRC (−10.5 vs. −7.8 kcal/mol), and pimelea factor P2 toward PIK3R1 (−11.0 vs. −8.2 kcal/mol) all showed significantly higher affinities than their corresponding co-crystallized ligands. Furthermore, procyanidin B2 demonstrated consistent binding to STAT1 and STAT3, confirming its role in modulating immune signals. Most of the PN phytochemicals show advantageous pharmacokinetic properties, including elevated anticipated gastrointestinal absorption and adherence to Lipinski’s rule of five, signifying favorable oral bioavailability and drug-like properties. Moreover, PN exhibits a remarkable multi-target binding capacity against both SARS-CoV-2 proteases and key host signaling proteins involved in immune regulation and inflammatory responses, as determined by this integrative network pharmacology and molecular docking investigation. Conclusions: PN’s prospects as a host-directed, antiviral treatment for COVID-19 are demonstrated by its coordinated modulation of the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways. These results necessitate further experimental and clinical validation, providing a solid computational basis for repurposing PN in the treatment of COVID-19. Full article

Phenolic acids and flavonoids remain attractive redox-active scaffolds in medicinal chemistry, where they are widely used for early-stage prioritization and intrinsic reactivity ranking. However, direct comparisons under harmonized conditions remain scarce, limiting structure-based assessment. Here, a structurally diverse panel of hydroxybenzoic acids, hydroxycinnamic acids, flavonoids, a flavanone, and synthetic comparators was profiled using Folin–Ciocalteu response, ABTS radical cation scavenging, DPPH radical scavenging, and reducing power assays. The data reveal pronounced assay dependence alongside clear structure–activity trends. Gallic acid showed the strongest DPPH scavenging (half-maximal inhibitory concentration, IC₅₀ = 4.45 µmol/L) and reducing power (17.26 µmol TE/mg), while quercetin was consistently active across all four endpoints. Eriocitrin (IC₅₀ = 2.47 µmol/L) and rutin (IC₅₀ = 2.66 µmol/L) were particularly effective in the ABTS assay, showing that glycosylation does not abolish cation-radical scavenging. Lipinski’s Rule of Five and Veber oral-bioavailability criteria place these findings within a drug-likeness context. The results also highlight the limitations of the Folin–Ciocalteu assay as a standalone measure of total phenolic content, since its response depends strongly on hydroxylation density. Rather than asserting therapeutic efficacy, this work provides a harmonized comparative dataset identifying phenolic substructures with the strongest and most consistent redox activity, together with the structural drivers underlying these patterns. Full article