Probing the alterations in mice cecal content due to high-fat diet.

The global prevalence of obesity more than doubled between 1990 and 2022. By 2022, 2.5 billion adults aged 18 and older were overweight, with over 890 million of them living with obesity. The urgent need for understanding the impact of high-fat diet, together with the demanding of analytical methods with low energy/chemicals consumption, can be fulfilled by rapid, high-throughput spectroscopic techniques. To understand the impact of high-fat diet on the metabolic signatures of mouse cecal contents, we characterized metabolite variations in two diet-groups (standard vs high-fat diet) using FTIR spectroscopy and multivariate analysis. Their cecal content showed distinct spectral features corresponding to high- and low-molecular-weight metabolites. Further quantification of 13 low-molecular-weight metabolites using liquid chromatography showed significant reduction in the production of short chain fatty acids and amino acids associated with high-fat diet samples. These findings demonstrated the potential of spectroscopy to follow changes in gut metabolites.

Disclosing gate-opening/closing events inside a flexible metal-organic framework loaded with CO2 by reactive and essential dynamics.

We have combined reactive molecular dynamics simulations with principal component analysis to provide a clearer view of the interactions and motion of the CO2 molecules inside a metal-organic framework and the movements of the MOF components that regulate storage, adsorption, and diffusion of the guest species. The tens-of-nanometer size of the simulated model, the capability of the reactive force field tuned to reproduce the inorganic-organic material confidently, and the unconventional use of essential dynamics have effectively disclosed the gate-opening/closing phenomenon, possible coordinations of CO2 at the metal centers, all the diffusion steps inside the MOF channels, the primary motions of the linkers, and the effects of their concerted rearrangements on local CO2 relocations.

Stability and potential degradation of the α',ß'-epoxyketone pharmacophore on ZnO nanocarriers: insights from reactive molecular dynamics and density functional theory calculations.

We investigate the structure and dynamics of a zinc oxide nanocarrier loaded with Carfilzomib, an epoxyketone proteasome inhibitor developed for treating multiple myeloma. We demonstrate that, even though both bare and functionalized zinc oxide supports have been used for drug delivery, their interactions with the reactive functional groups of the ligands could be detrimental. This is because pharmacophores like α',ß'-epoxyketones should preserve the groups required for the drug activity and be capable of leaving the vehicle at the target site. Earlier studies showed that even when ZnO is functionalized with oleic acid surfactants, the drug could reach parts of the surface and remain stably adsorbed. Herein, we have used reactive molecular dynamics simulations and quantum chemistry calculations to explore the potential interactions of the Carfilzomib functional groups with the typical surfaces of ZnO supports. We have found that Carfilzomib can adsorb on the (0001)Zn-terminated polar surface through the carbonyl oxygens and the epoxyketone moiety. These strong connections could prevent the drug release and induce the epoxy ring opening with its consequential inactivation. Therefore, regulating the dosage to maintain the desired level of drug bioavailability is paramount. These findings emphasize the need for appropriate carrier functionalizations to efficiently entrap, transport, and release the cargo at the target sites and the crucial role played by predictive/descriptive computational techniques to complement and drive experiments to the most appropriate selections of the materials to optimize drug delivery.

Exploring the mechanisms of drug-delivery by decorated ZnO nanoparticles through predictive ReaxFF molecular dynamics simulations.

Herein, we study the assembling of a drug delivery nanocarrier through reactive molecular dynamics simulations based on an appropriately tuned force field. First, we focus on the combination of the various components (all selected in agreement with experiments), namely nanoparticle (ZnO), functional chains (oleic acid), drug (carfilzomib), and solvent molecules (ethanol), and then on the ability of the assembled nanotool to release its cargo in a physiological environment (water). The simulation results reveal that reactivity is crucial for characterizing the stability of the functionalized ZnONP, its dynamics, and its interactions with lipid chains and drug molecules. The chains are stably chemisorbed on the ZnONP through monodentate or bidentate binding of the carboxyls to the Zn atoms (the hydrogens are released to the surface oxygens). Chains' self-interactions reinforce the lipid cover's stability and distribution on the ZnONP interface. The added drug migrates from the solution to the nano assembly and is captured by the lipids. The molecules are entrapped among the oleic acid chains and adsorbed on the uncoated regions of the nanoparticle surface, partially physisorbed or chemisorbed. The analysis of the simulations confirms that the supramolecular assembly is compact and stable in ethanol. However, upon injection into the water, the size of the aggregate gradually increases, and the lipids start to swell with the aqueous medium. The system evolves towards an unpacked structure where the chains are elongated, separated, and prone to release the cargo depending on local water activity and depth of cargo insertion. All the results agree with the literature confirming the reliability of our predictive computational procedure for disclosing the structure and dynamics of complex materials relevant to the medicinal chemistry field.