Maher S. Alwethaynani

The papain-like protease (PL[ ] of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) plays a key role in viral polyprotein processing and suppression of host innate response, making it a valuable target for the development of anti-viral drugs. However, the availability of potent small-molecule inhibitors of PL[ ] remains limited. The current study was designed to synthesize novel indole-tagged thia/oxadiazole scaffolds (10–23) and their inhibition profile against PL[ ] was tested, with GRL0617 used as a reference inhibitor. The evaluation revealed a broad spectrum of inhibitory potency, with IC[ ] values ranging from 0.7934 [ ]M to 23.79 [ ]M. Remarkably, compounds 13 (IC[ ] 0.7934 [ ]M), 11 (IC[ ] 1.118 [ ]M), and 18 (IC[ ] 1.446 [ ]M) demonstrated superior inhibitory potency relative to the reference inhibitor GRL0617 (IC[ ] 2.40 [ ]M). Based on structure–activity relationship (SAR) investigations, the alterations to the aryl ring substituents attached to the thia/oxadiazole scaffold were identified to be the key factor for modulating inhibitory potency. The molecular docking study of the most active compound 13 demonstrated a favorable binding conformation within the PL[ ], highlighted by stable hydrogen bonding and hydrophobic interactions with key catalytic residues, thereby enhancing inhibitory potency. Additionally, Density Functional Theory (DFT) calculations and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analyses of potent compound 13 showed favorable electronic properties and suitable pharmacokinetic properties, supporting its potential for further optimization. Altogether, these findings identify compound 13 as a potent early-stage enzymatic hit that provides a valuable starting point for further structural optimization toward the development of improved SARS-CoV-2 PL[ ] inhibitors.

Twelve new pyrazole-linked carbonitrile-based Schiff base derivatives have been prepared in the present study following a two-step pathway of reactions and tested as a dual inhibitor of urease and thymidine phosphorylase (TP). The main target of this study was to develop structurally simple yet biologically active pyrazole-based scaffolds for targeting enzymes involved in bacterial infections and cancer-related angiogenesis. The originality of this research lies in the rational synthesis of a pyrazole–carbonitrile core bearing Schiff base functionality, and in the thorough examination of the structure–activity relationship (SAR) through the in vitro, in silico and quantum chemical studies. The compounds synthesized were structurally verified by the use of the NMR spectroscopy of ¹ H and [ ]C and screened against enzyme inhibition. Some of the derivatives showed better activity than the standard inhibitors, with compounds 4 (13.47 ± 1.12 [ ]M for urease; 4.04 ± 1.78 [ ]M for TP), 11 (14.75 ± 1.53 [ ]M; 4.42 ± 0.98 [ ]M), and 8 (17.93 ± 1.98 [ ]M; 5.73 ± 2.16 [ ]M). The results of molecular docking showed favorable binding interactions in the active sites of urease (PDB ID: 4UBP) and TP (PDB ID: 4EAD). In order to confirm binding stability, 100 ns molecular dynamics simulations were conducted, which confirmed stable ligand–protein complexes, especially between compound 8 and urease and compound 4 and TP. DFT calculations were used to understand electronic stability and reactivity, and ADME analysis identified drug-like properties acceptable for the lead compounds.

Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) inhibitors are used to increase acetylcholine levels in current symptomatic treatments for Alzheimer’s disease (AD), which is still the most common neurodegenerative illness. Through the synthesis and thorough assessment of a novel series of Imidazo-pyrazinone derivatives (8a–8l), this study sought to identify and create highly effective cholinesterase inhibitors. Using donepezil as the standard reference medication, the produced compounds were tested in vitro for their inhibitory activity against both AChE and BuChE (AChE IC50 ([ ]M) 2.16 ± 0.12, BuChE IC50 ([ ]M) 4.50 ± 0.11). The findings showed that most of the recently created derivatives had better inhibitory activity than the reference medication. Compound 8h was the most effective dual inhibitor in the series, outperforming Donepezil with an AChE IC[ ] of 1.22 ± 0.30 and a BuChE of 3.75 ± 1.20. Derivatives with electron-withdrawing groups, such as the fluoro substituent, particularly at the meta-position, and these strengthen interactions around the enzyme’s active site, demonstrated the greatest levels of inhibition, according to the Structure–Activity Relationship (SAR) studies. The ortho-position hydroxyl (–OH) phenolic group in compound 8h was also found to be an important structural feature that increased potency by encouraging helpful hydrogen bonding with catalytic residues. In order to investigate the binding mode, reliability and electronic characteristics of the most active compounds, molecular docking and Density Functional Theory (DFT) calculations have been carried out in addition to the studies. The results of the experiment were supported by the docking analysis, which verified the advantageous penetration of compound 8h through the active site. Additionally, the most promising candidates’ acceptable pharmacokinetic profiles and drug-likeness were predicted through Absorption, Distribution, Metabolism and Excretion (ADME) evaluation. To sum up, compound 8h, a novel imidazo-pyrazinone derivative, is a potent dual AChE and BuChE inhibitor that deserves more in vivo investigation as a potential lead compound for Alzheimer’s disease treatment.

In this study, an aqueous extract of Spirulina platensis was utilized as a reducing and stabilizing agent for the green synthesis of silver‐zinc oxide nanocomposites (Ag‐ZnO). The S. platensis extract was optimized at a concentration of 0.5%, stored at 4°C and centrifuged at 6000 rpm for 5 min. Ultraviolet–visible spectroscopy of the extract showed a broad absorbance band in the 330‐ to 380‐nm region and a shoulder in the 520‐ to 620‐nm range, corresponding to bioactive metabolites. The formation of silver‐zinc oxide nanocomposites was confirmed by characteristic absorbance in the 300‐ to 400‐nm region under optimized conditions. Particle size analysis using a Zetasizer revealed an average particle size of approximately 204 nm with a polydispersity index of 0.28. Functional groups, crystallinity, and surface morphology were characterized using Fourier transform infrared spectroscopy, X‐ray diffraction, and scanning electron microscopy. Due to increasing concerns over antibiotic resistance, the antibacterial potential of the synthesized nanocomposites was evaluated by the disk diffusion method showing a maximum zone of inhibition of 35 ± 0.4 nm against Pseudomonas aeruginosa at 13 μg/mL. The Ag‐ZnO nanocomposites exhibited a notable antioxidant activity, indicating a concentration‐dependent DPPH radical scavenging activity with a maximum inhibition of 67.3% at 517 nm, compared to 60.12 for ascorbic acid. Furthermore, cytotoxic evaluation against the BT‐549 breast cancer cell line revealed a half‐maximal inhibitory concentration (IC ₅₀ ) of 6.401 μg/mL. These findings indicate that S. platensis –mediated silver‐zinc oxide nanocomposites exhibit promising biological activity.

Cow’s Milk Allergy (CMA) remains one of the most common food allergies, particularly in children, with several milk-derived proteins identified as the major allergens responsible for IgE-mediated hypersensitivity reactions, including [ ]-lactalbumin (Bos d 4), [ ]-lactoglobulin (Bos d 5), serum albumin (Bos d 6) and [ ]S1-casein (Bos d 9). Conventional therapies often carry limitations such as incomplete efficacy or safety concerns, necessitating the exploration of safer alternatives. This study aimed to evaluate probiotic-derived fatty acid metabolites, with a particular focus on linoelaidic acid, as potential therapeutic agents against milk allergens. A GC–MS profile of probiotic metabolites was constructed, followed by allergenicity screening of milk proteins. The allergen proteins were retrieved and subjected to molecular docking with identified fatty acids. Linoelaidic acid exhibited strong binding affinities (−8.4 kcal/mol to −9.1 kcal/mol) with major allergens and demonstrated stability across 100 ns MD simulations, suggesting potential for nutraceutical application. Molecular dynamics (100 ns) confirmed the structural stability and compactness of the docked complexes, supported by RMSD stabilization (0.7–0.9 nm for [ ]-lactalbumin, 0.6–0.7 nm for [ ]-lactoglobulin, 2.5 nm for [ ]S1-casein and 0.34 nm for serum albumin) and hydrogen bonding consistency ([ ]300 in [ ]S1-casein complex, [ ]1350 in serum albumin). Pharmacokinetic profiling through SwissADME demonstrated favorable drug-like properties, while ProTox-II analysis classified linoelaidic acid as nontoxic (Drug Class VI). These findings suggest that linoelaidic acid holds strong therapeutic potential for mitigating CMA. This study is based on computational predictions and requires experimental validation to confirm their biological relevance and therapeutic potential. Future prospects include in vitro and in vivo validation to confirm its immunomodulatory and clinical efficacy.

KRAS mutations cause a variety of malignancies, with the KRAS-G12C variation serving as a key oncogenic target. Despite the approval of Sotorasib for KRAS G12C-mutated NSCLC, resistance and poor efficacy indicate the need for new inhibitors. This study screened over 11,800 marine-derived chemicals from the CMNPD database using a computer-assisted workflow. Following drug-likeness filtering and virtual screening, three candidates (CMNPD27430, CMNPD23547 and CMNPD10958) demonstrated higher binding affinities to KRAS-G12C than Sotorasib. Molecular dynamics simulations (100 ns) confirmed complex stability, which was validated by RMSD, RMSF, Rg, SASA and hydrogen bonding analysis. ADMET profiling also revealed favorable drug-like and pharmacokinetic characteristics. These findings suggest that marine natural compounds are viable scaffolds for the future development of KRAS-G12C inhibitors.

Upon careful re-examination of the RCSB entry for PDB ID: 7C36 prompted by an insightful reader, the authors confirm that this structure corresponds to RBMS1 (UniProt: P29558), a single-stranded DNA-binding protein involved in regulation of the c-MYC promoter, and not to the human c-Myc protein (UniProt: P01106) as originally stated in the manuscript. The PDB annotation as a “c-Myc DNA-binding protein complex” unfortunately led to a misinterpretation during structural selection. The authors acknowledge that the structure used in docking was not a crystallographic structure of c-Myc. Therefore, the docking results and interaction analyses described as “MYC–ligand” interactions are structurally attributable to RBMS1 rather than c-Myc. Any conclusions regarding direct protein–ligand interactions at the c-Myc protein interface are consequently not supported by the selected structure. The publisher hereby retracts the manuscript.