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Multiple diseases are treated with carbohydrate-based medicinal products worldwide. Direct regioselective acylation of methyl α-D-mannopyranoside (MDMP) derivatives 2-6 afforded from the 6-O-butyryl derivative. This isolated 6-O-derivative was converted to 2,3,4-tri-O-acyl derivatives, and the resulting compounds were analyzed using FTIR, 1H-NMR, 13C-NMR, and elemental analysis. The acylated derivatives showed moderate to good antimicrobial activity. Cytotoxicity assessment indicated that compound 2 had the lowest toxicity. A SAR study demonstrated that lauroyl and myristoyl acyl chains combined with mannopyranose were particularly effective against bacteria. In this context, molecular docking analysis demonstrated crucial interactions involved in assessing the binding affinity of ligands 1-6 for the active sites of Escherichia coli (4XO8) and Aspergillus flavus (1R51). A 100-ns molecular dynamics simulation showed that all the compounds were stable at the active site of protein 1R51. In silico ADMET prediction revealed greater drug similarity for MDMP derivatives. The results of this investigation may help create MDMP derivative-based multidrug-resistant antimicrobial agents.Highlights Methyl α-D-mannopyranoside (MDMP) derivatives were designed, and synthesized, and their structures were ascertained via spectral analyses.MDMPs were assessed in vitro to identify potential antibacterial or antifungal potential antimicrobial candidate(s) against human and plant organisms.Molecular docking results revealed significant interactions between compounds 1-6 and the active sites of Escherichia coli (4XO8) and Aspergillus flavus (1R51).A 100 ns molecular dynamic simulation demonstrated that the docked ligand–receptor complex had better dynamic stability, as determined through the RMSD, RMSF, SASA, and Rg profiles.ADMET prediction revealed an improved drug-likeness profile for all MDMP derivatives.

Methyl α-D-mannopyranoside (MAM) is a naturally occurring carbohydrate derivative that has gained attention in drug discovery due to its potential therapeutic applications, particularly as an antifungal agent. In this study, we employed a computational approach to investigate the interactions between MAM and two Candida albicans antifungal proteins, 1IYL and 1AI9, through molecular docking simulations. Furthermore, we performed a PASS (Prediction of Activity Spectra for Substances) analysis to predict MAM potential biological activities, explored the pharmacokinetic properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles, and optimized the MAM using the density functional theory (DFT) method. The molecular docking results revealed favorable binding interactions between MAM and the active sites of the 1IYL and 1AI9 proteins, suggesting potential antifungal activity. Additionally, the ADMET profiles indicated low toxicity and suitable drug-like properties, such as moderate metabolic stability and minimal risk of adverse effects. Furthermore, DFT optimization was performed to investigate the molecular geometry and electronic properties of MAM. The optimization results provided valuable information on the stability and reactivity of MAM, enabling a better understanding of its chemical behavior and potential modifications for enhanced activity. Finally, PASS prediction was employed to evaluate MAM's potential biological activities beyond its antifungal properties. The analysis revealed several potential activities, including antibacterial, antiviral, and immunomodulatory effects, expanding the scope for future research and therapeutic applications. In conclusion, this computational study sheds light on the molecular interactions, pharmacokinetic properties, ADMET profiles, DFT optimization, and PASSES predictions of MAM. These findings highlight the potential of MAM as a promising antifungal agent with favorable pharmacological properties.

Distributed Bragg reflectors (DBRs) based on alternating layers of porous and non-porous GaN have previously been fabricated at the wafer-scale in heteroepitaxial GaN layers grown on sapphire substrates. Porosification is achieved via the electrochemical etching of highly Si-doped layers, and the etchant accesses the n+-GaN layers through nanoscale channels arising at threading dislocations that are ubiquitous in the heteroepitaxial growth process. Here, we show that the same process applies to GaN multilayer structures grown on silicon substrates. The reflectance of the resulting DBRs depends on the voltage at which the porosification process is carried out. Etching at higher voltages yields higher porosities. However, while an increase in porosity is theoretically expected to lead to peak reflectance, in practice, the highest reflectance is achieved at a moderate etching voltage because etching at higher voltages leads to pore formation in the nominally non-porous layers, pore coarsening in the porous layers, and in the worst cases layer collapse. We also find that at the high threading dislocation densities present in these samples, not all dislocations participate in the etching process at low and moderate etching voltages. However, the number of dislocations involved in the process increases with etching voltage. [ABSTRACT FROM AUTHOR]

We here report the purification of a novel member of the galectin family, the β-galactoside-binding lectin hRTL, from the marine sponge Chondrilla australiensis. The hRTL lectin is a tetrameric proto-type galectin with a subunit molecular weight of 15.5 kDa, consisting of 141 amino acids and sharing 92% primary sequence identity with the galectin CCL from the congeneric species C. caribensis. Transcriptome analysis allowed for the identification of additional sequences belonging to the same family, bringing the total number of hRTLs to six. Unlike most other galectins, hRTLs display a 23 amino acid-long signal peptide that, according to Erdman degradation, is post-translationally cleaved, leaving an N-terminal end devoid of acetylated modifications, unlike most other galectins. Moreover, two hRTLs display an internal insertion, which determines the presence of an unusual loop region that may have important functional implications. The characterization of the glycan-binding properties of hRTL revealed that it had high affinity towards TF-antigen, sialyl TF, and type-1 N-acetyl lactosamine with a Galβ1-3 structure. When administered to DLD-1 cells, a colorectal carcinoma cell line expressing mucin-associated TF-antigen, hRTL could induce glycan-dependent cytotoxicity.

This work describes the synthesis, characterization, and in vitro and in silico evaluation of the biological activity of new functionalized isoxazole derivatives. The structures of all new compounds were analyzed by IR and NMR spectroscopy. The structures of 4c and 4f were further confirmed by single crystal X-ray and their compositions unambiguously determined by mass spectrometry (MS). The antibacterial effect of the isoxazoles was assessed in vitro against Escherichia coli, Bacillus subtilis, and Staphylococcusaureus bacterial strains. Isoxazole 4a showed significant activity against E. coli and B. subtilis compared to the reference antibiotic drugs while 4d and 4f also exhibited some antibacterial effects. The molecular docking results indicate that the synthesized compounds exhibit strong interactions with the target proteins. Specifically, 4a displayed a better affinity for E. coli, S. aureus, and B. subtilis in comparison to the reference drugs. The molecular dynamics simulations performed on 4a strongly support the stability of the ligand–receptor complex when interacting with the active sites of proteins from E. coli, S. aureus, and B. subtilis. Lastly, the results of the Absorption, Distribution, Metabolism, Excretion and Toxicity Analysis (ADME-Tox) reveal that the molecules have promising pharmacokinetic properties, suggesting favorable druglike properties and potential therapeutic agents.

SeviL, a galactoside-binding lectin previously isolated from the mussel Mytilisepta virgata, was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel β-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.

It has been more than four years since the first report of SARS-CoV-2, and humankind has experienced a pandemic with an unprecedented impact. Moreover, the new variants have made the situation even worse. Among viral enzymes, the SARS-CoV-2 main protease (Mpro) has been deemed a promising drug target vs. COVID-19. Indeed, Mpro is a pivotal enzyme for viral replication, and it is highly conserved within coronaviruses. It showed a high extent of conservation of the protease residues essential to the enzymatic activity, emphasizing its potential as a drug target to develop wide-spectrum antiviral agents effective not only vs. SARS-CoV-2 variants but also against other coronaviruses. Even though the FDA-approved drug nirmatrelvir, a Mpro inhibitor, has boosted the antiviral therapy for the treatment of COVID-19, the drug shows several drawbacks that hinder its clinical application. Herein, we report the synthesis of new thiazolidine-4-one derivatives endowed with inhibitory potencies in the micromolar range against SARS-CoV-2 Mpro. In silico studies shed light on the key structural requirements responsible for binding to highly conserved enzymatic residues, showing that the thiazolidinone core acts as a mimetic of the Gln amino acid of the natural substrate and the central role of the nitro-substituted aromatic portion in establishing π-π stacking interactions with the catalytic His-41 residue.

Carbohydrates derivatives played an important and vital role in a large part to design new potential drug against various pathogens, in medicinal chemistry. Also, monosaccharide derivatives are very useful in biological chemistry because monosaccharide binding agents were shown to possess antiviral, antibacterial, and antifungal activity towards HIV, Dengue coronaviruses, and many members of the family Enterobacteriaceae, including strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Shigella flexneri, and Enterobacter aerogenes. The present study was therefore interesting in identifying the binding affinity of a series of monosaccharides previously synthesized through their physicochemical and pharmacokinetic properties. These monosaccharides are derivatives of methyl-β-D-galactopyranoside (MGP) coupled to the protein deacetoxycephalosporin C synthase (DAOCS) of Streptomyces clavuligerus (1RXF). Molecular docking study against DAOCS proteins (PDB ID: 1RXF) was performed assess the antimicrobial activities of these derivatives along with antiviral prediction. The results of molecular docking studies showed that derivatives 8 and 10 both presented the highest score (-7.2 kcal/mol), reflecting their good binding affinity toward the active pocket of the pathogen S. clavuligerus (1RXF). They are found to be potent antimicrobial agents. These findings were further validated in dynamics (200 ns) milieu and intermolecular stability was evaluated via highly acceptable Molecular Mechanics Poisson-Boltzmann Surface Area (MMPB)/Molecular Mechanics/Generalized Born Surface Area (GBSA) binding free energies estimation methods. The dynamics of the complexes are highly stable with the strengthening of docked interactions as highlighted by MMPB/GBSA method (net binding energy < −40 kcal/mol). Density functional theory (DFT) calculations were carried out on the derivatives of MGP in order to determine the partial atomic charges, electronic energies, enthalpies, entropies and polarizability, at the B3LYP/3-21G level. The in silico ADMET prediction carried out provided access to the bioactivity and toxicity parameters which established that most of the different ligands designed are safe to use as drugs. This in silico study provided an overall view of the possible pharmacological and therapeutic profile of MGP derivatives. It therefore, paved the way for the discovery of promising next-generation drugs against pathogenic microbes.

The pursuit of innovative combinations for the development of novel antimicrobial and antiviral medications has garnered worldwide interest among scientists in recent times. Monosaccharides and their glycosides, such as methyl α-d-mannopyranoside derivatives, play a significant role in the potential treatment of viral respiratory pathologies. This study was undertaken to investigate and assess the synthesis and spectral characterization of methyl α-d-mannopyranoside derivatives 2–6, incorporating various aliphatic and aromatic groups. The investigation encompassed comprehensive in vitro antimicrobial screening, examination of physicochemical properties, molecular docking analysis, molecular dynamics simulations, and pharmacokinetic predictions. A unimolar one-step cinnamoylation reaction was employed under controlled conditions to produce methyl 6-O-cinnamoyl-α-d-mannopyranoside 2, demonstrating selectivity at the C-6 position. This represented a pivotal step in the development of potential antimicrobial derivatives based on methyl α-d-mannopyranoside. Subsequently, four additional methyl 6-O-cinnamoyl-α-d-mannopyranoside derivatives were synthesized with reasonably high yields. The chemical structures of these novel analogs were confirmed through a thorough analysis of their physicochemical properties, elemental composition, and spectroscopic data. In vitro antimicrobial assays were conducted against six bacterial strains and two fungal strains, revealing promising antifungal properties of these methyl α-d-mannopyranoside derivatives in comparison to their antibacterial activity. Moreover, cytotoxicity testing revealed that the compounds are less toxic. Further supporting these findings, molecular docking studies were performed against the H5N1 influenza A virus, indicating significant binding affinities and nonbonding interactions with the target protein 6VMZ. Notably, compounds 4 (−7.2) and 6 (−7.0) exhibited the highest binding affinities. Additionally, a 100 ns molecular dynamics simulation was conducted to assess the stability of the complex formed between the receptor 6VMZ and methyl α-d-mannopyranoside derivatives under in silico physiological conditions. The results revealed a stable conformation and binding pattern within the stimulating environment. In silico pharmacokinetic and toxicity assessments of the synthesized molecules were performed using Osiris software (version 2.9.1). Compounds 4 and 6 demonstrated favorable computational and pharmacological activities, albeit with a low drug score, possibly attributed to their higher molecular weight and irritancy. In conclusion, this study showcases the synthesis and evaluation of methyl α-d-mannopyranoside derivatives as promising candidates for antimicrobial and antifungal agents. Molecular docking and dynamics simulations, along with pharmacological predictions, contribute to our understanding of their potential therapeutic utility, although further research may be warranted to address certain pharmacological aspects.

Marine compounds constitute a diverse and invaluable resource for the discovery of bioactive substances with promising applications in the pharmaceutical development of anti-inflammatory and antibacterial agents. In this study, a comprehensive methodology was employed, encompassing pharmacophore modeling, virtual screening, in silico ADMET assessment (encompassing aspects of absorption, distribution, metabolism, excretion, and toxicity), and molecular dynamics simulations. These methods were applied to identify new inhibitors targeting the Hsp90 protein (heat shock protein 90), commencing with a diverse assembly of compounds sourced from marine origins. During the virtual screening phase, an extensive exploration was conducted on a dataset comprising 31,488 compounds sourced from the CMNPD database, characterized by a wide array of molecular structures. The principal objective was the development of structure-based pharmacophore models, a valuable approach when the pool of known ligands is limited. The pharmacophore model DDRRR was successfully constructed within the active sites of the Hsp90 crystal structure. Subsequent docking studies led to the identification of six compounds (CMNPD 22591, 9335, 10015, 360799, 15115, and 20988) demonstrating substantial binding affinities, each with values below −8.3 kcal/mol. In the realm of in silico ADMET predictions, five of these compounds exhibited favorable pharmacokinetic properties. Furthermore, molecular dynamics simulations and total binding energy calculations using MM-PBSA indicated that these marine-derived compounds formed exceptionally stable complexes with the Hsp90 receptor over a 100-nanosecond simulation period. These findings underscore the considerable potential of these novel marine compounds as promising candidates for anticancer and antimicrobial drug development.

The rising antimicrobial resistance crisis has diminished the effectiveness of traditional antibiotics against pathogenic bacteria. This study addresses this urgent challenge by exploring the antibacterial potential of novel quinolone derivatives (1–33). Using computational in silico modeling to simulate biological interactions, we aimed to identify candidates with potent antibacterial activity. A total of 33 quinolone derivatives were assessed for their physicochemical properties and effectiveness against a range of clinically relevant pathogens, including methicillin‐resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Streptococcus pneumoniae, and Enterococcus faecalis. Molecular docking studies identified compounds 28, 29, 32, and 33 as having notable binding affinities, particularly against MRSA. Further molecular dynamics simulations of compound 29 confirmed its favorable stability and potential for disrupting MRSA, reinforcing the docking results and showing strong alignment with in vitro findings. These findings position compound 29 as a promising lead for developing alternative MRSA therapies and underscore the need for further in vivo studies to evaluate its therapeutic potential. [ABSTRACT FROM AUTHOR]