Binding of voriconazole aptamers and modulation of binding by cyclodextrins

Selection of DNA Aptamers for Mycophenolic Acid and Mycophenolate Mofetil Detection in Human Serum.

Long-Acting Lipoglycopeptide Treatment of Invasive Gram-Positive Infections

Antifungal activity of the nucleoside mimetic 5-fluorouridine against Candidozyma auris and Candida species

ABSTRACT The emergence of multidrug-resistant Candidozyma auris has created an urgent need for antifungals with novel mechanisms of action. We screened 121 nucleoside and nucleobase derivatives against C. auris and other clinically relevant Candida species to identify effective antimetabolite scaffolds. Among all compounds tested, only the C-5-fluorinated nucleosides 5-fluorouridine (5-FU) and 5-fluorocytidine exhibited potent antifungal activity. 5-FU demonstrated consistently low minimum inhibitory concentrations (0.5–10 µg/mL) across multiple Candida species, including fluconazole-resistant strains, and displayed fungicidal activity against C. auris at concentrations lower than several frontline antifungals. Uridine rescue assays confirmed competitive interference with endogenous uridine metabolism. Checkerboard assays revealed synergistic or additive interactions between 5-FU and clinically used azoles and echinocandins. Toxicity evaluation using plant, nematode, and human cell models showed minimal cytotoxicity even at concentrations far exceeding antifungal minimum inhibitory concentrations. In silico docking analyses revealed dual inhibition of thymidylate synthase and RNA polymerase III, explaining the fungicidal phenotype and broad-spectrum efficacy. These findings identify 5-fluorouridine as a promising antifungal candidate and establish C-5-halogenated nucleosides as a privileged scaffold for antifungal drug development.

Complexation of teicoplanin and sulfobutylether-β-cyclodextrin: experimental and theoretical insights into the potential relevance of their molecular interaction to teicoplanin pharmacokinetics.

Teicoplanin (TEIC) is widely used in clinical settings to treat serious bacterial infections. This lipoglycopeptide antimicrobial is characterized by a long elimination half-life because of high protein binding owing to its lipophilic side chain. We recently found that the blood concentration of TEIC was significantly decreased when posaconazole was concomitantly administered intravenously rather than orally. We hypothesized that sulfobutylether-β-cyclodextrin (SBE-β-CD), a pharmaceutical excipient contained in posaconazole injectable formulation, may be the potential contributor to this phenomenon. Here, we investigated the molecular interaction between TEIC and SBE-β-CD by theoretical and experimental strategies to examine this possibility and elucidate the underlying mechanisms. Nuclear magnetic resonance analysis confirmed the encapsulation of the TEIC hydrophobic tail by the SBE-β-CD hydrophobic cavity, thereby forming a complex with 1:1 stoichiometry and appreciable binding affinity. These findings were further supported by docking simulations and subsequent quantum chemical calculations. Non-covalent interaction analysis visualized the regions and features of their supramolecular interactions. Computational and in vitro studies highlighted the significant contribution of the TEIC hydrophobic side chain in its binding to human serum albumin. Our results collectively indicate that the direct molecular interaction, whereby the hydrophobic cavity of SBE-β-CD encapsulates most of the hydrophobic side chain of TEIC, can reduce TEIC protein binding and may consequently affect its pharmacokinetics.

Computational Discovery of Novel CYP51 Inhibitors for Antifungal Therapy Against Aspergillus fumigatus.

Lanosterol 14-alpha demethylase (CYP51), encoded by the Erg11 gene, is a crucial enzyme in pathogenic fungi. It catalyzes the demethylation of lanosterol to ergosterol, a vital component of fungal cell membranes. Inhibition of CYP51 disrupts ergosterol biosynthesis, compromises membrane integrity, and inhibits fungal growth, making it a key target for antifungal therapy. In this study, we employed a comprehensive computational approach comprising molecular docking, drug-likeness analysis, dynamics simulations, pharmacophoric feature modeling, ADMET profiling, and pharmacokinetic (PK) simulations to identify novel CYP51 inhibitors from a library of 1,200 plant-derived metabolites. Of these, 211 compounds exhibited stronger binding affinities than voriconazole, a widely used antifungal agent. The top 10 metabolites showed strong interactions with key substrate recognition sites (SRS1, SRS2, SRS4, and SRS6) of CYP51. MD simulations of the top three candidates, Boeravinone D, Nimbidin, and 7-acetyl neotrichilenone, revealed stable binding conformations primarily driven by non-polar interactions, as confirmed by MM/GBSA binding free energy calculations. Notably, Nimbidin exhibited the most favorable binding energetics, supported by Gibbs free energy and hydrogen bonding analyses. Principal component analysis (PCA) further indicated distinct and stable dynamic behaviors of the ligand-protein complexes. Pharmacokinetic simulations suggested that Boeravinone D and Nimbidin may maintain prolonged plasma concentrations, indicating strong therapeutic potential. All three candidates showed favorable ADMET profiles, although 7-acetyl neotrichilenone may require optimization to improve solubility. These findings identify Boeravinone D, Nimbidin, and 7-acetyl neotrichilenone as promising CYP51 inhibitors. Further in vitro and in vivo studies are warranted to validate their antifungal efficacy and advance them as potential therapeutic agents.

Novel salicylamido sulfonamides as CD73 immune checkpoint inhibitors: Synthesis and in vitro biological evaluation.

In silico ADME analysis indicated that both lead compounds possess favourable drug-like properties, with no Lipinski's rule-of-five violations, balanced lipophilicity, and acceptable predicted oral absorption, supporting their pharmacokinetic potential.