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A Dispersion Corrected DFT Investigation of the Inclusion Complexation of Dexamethasone with β-Cyclodextrin and Molecular Docking Study of Its Potential Activity against COVID-19.

ABSTRACT: The encapsulation mode of dexamethasone (Dex) into the cavity of β-cyclodextrin (β-CD), as well as its potential as an inhibitor of the COVID-19 main protease, were investigated using density functional theory with the recent dispersion corrections D4 and molecular docking calculations. Independent gradient model and natural bond orbital approaches allowed for the characterization of the host-guest interactions in the studied systems. Structural and energetic computation results revealed that hydrogen bonds and van der Waals interactions played significant roles in the stabilization of the formed Dex@β-CD complex. The complexation energy significantly decreased from -179.50 kJ/mol in the gas phase to -74.14 kJ/mol in the aqueous phase. A molecular docking study was performed to investigate the inhibitory activity of dexamethasone against the COVID-19 target protein (PDB ID: 6LU7). The dexamethasone showed potential therapeutic activity as a SARS CoV-2 main protease inhibitor due to its strong binding to the active sites of the protein target, with predicted free energy of binding values of -29.97 and -32.19 kJ/mol as calculated from AutoDock4 and AutoDock Vina, respectively. This study was intended to explore the potential use of the Dex@β-CD complex in drug delivery to enhance dexamethasone dissolution, thus improving its bioavailability and reducing its side effects.

SUBMITTER: Belhocine Y

PROVIDER: S-EPMC8708408 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Inclusion Complexation of Organic Micropollutants with β-Cyclodextrin.

Project description:Recently, β-cyclodextrin (βCD)-based polymers with enhanced adsorption kinetics and high removal capacity of organic micropollutants (OMPs) and uptake rates have been synthesized and tested experimentally. Although the exact physical-chemical mechanisms via which these polymers capture the various types of OMPs are not yet fully understood, it is suggested that the inclusion complex formation of OMPs with βCD is very important. In this study, the inclusion complex formation of OMPs with βCD in an aqueous solution is investigated by using the well-established attach-pull-release method in force field-based molecular dynamics simulations. A representative set of OMPs is selected based on the measured occurrences in surface and ground waters and the directives published by the European Union. To characterize the formation of the inclusion complex, the binding free energies, enthalpies, and entropies are computed and compared to experimental values. It is shown that computations using the q4md-CD/GAFF/Bind3P force field combination yield binding free energies that are in reasonable agreement with the experimental results for all OMPs studied. The binding enthalpies are decomposed into the main contributing interaction types. It is shown that, for all studied OMPs, the van der Waals interactions are favorable for the inclusion complexion and the hydrogen bond formation of the guest with the solvent and βCD plays a crucial role in the binding mechanism. Our findings show that MD simulations can adequately describe the inclusion complex formation of βCD with OMPs, which is the first step toward understanding the underlying mechanisms via which the βCD-based polymers capture OMPs.

| S-EPMC7037149 | biostudies-literature

Evaluation and Characterization of Curcumin-β-Cyclodextrin and Cyclodextrin-Based Nanosponge Inclusion Complexation.

Project description:Cyclodextrin polymers and cyclodextrin-based nanosponges have been widely investigated for increasing drug bioavailability. This study examined curcumin's complexation stability and solubilization with β-cyclodextrin and β-cyclodextrin-based nanosponge. Nanosponges were prepared through the cross-linking of β-cyclodextrin with different molar ratios of diphenyl carbonate. Phase solubility experiments were conducted to evaluate the formed complexes and evaluate the potential of using β-cyclodextrin and nanosponge in pharmaceutical formulations. Furthermore, physicochemical characterizations of the prepared complexes included PXRD, FTIR, NMR, and DSC. In addition, in vitro release studies were performed for the prepared formulations. The formation of β-cyclodextrin complexes enhanced curcumin solubility up to 2.34-fold compared to the inherent solubility, compared to a 2.95-fold increment in curcumin solubility when loaded in β-cyclodextrin-based nanosponges. Interestingly, the stability constant for curcumin nanosponges was (4972.90 M-1), which was ten times higher than that for the β-cyclodextrin complex, where the value was 487.34 M-1. The study results indicated a decrease in the complexation efficiency and solubilization effect with the increased cross-linker amount. This study's findings showed the potential of using cyclodextrin-based nanosponge and the importance of studying the effect of cross-linking density for the preparation of β-cyclodextrin-based nanosponges to be used for pharmaceutical formulations.

| S-EPMC8658939 | biostudies-literature

Computational Insights Into the Influence of Substitution Groups on the Inclusion Complexation of β-Cyclodextrin.

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| S-EPMC8176092 | biostudies-literature

Enhancement of naringenin bioavailability by complexation with hydroxypropyl-?-cyclodextrin. [corrected].

Project description:The abundant flavonoid aglycone, naringenin, which is responsible for the bitter taste in grapefruits, has been shown to possess hypolipidemic and anti-inflammatory effects both in vitro and in vivo. Recently, our group demonstrated that naringenin inhibits hepatitis C virus (HCV) production, while others demonstrated its potential in the treatment of hyperlipidemia and diabetes. However, naringenin suffers from low oral bioavailability critically limiting its clinical potential. In this study, we demonstrate that the solubility of naringenin is enhanced by complexation with ?-cyclodextrin, an FDA approved excipient. Hydroxypropoyl-?-cyclodextrin (HP?CD), specifically, increased the solubility of naringenin by over 400-fold, and its transport across a Caco-2 model of the gut epithelium by 11-fold. Complexation of naringenin with HP?CD increased its plasma concentrations when fed to rats, with AUC values increasing by 7.4-fold and C(max) increasing 14.6-fold. Moreover, when the complex was administered just prior to a meal it decreased VLDL levels by 42% and increased the rate of glucose clearance by 64% compared to naringenin alone. These effects correlated with increased expression of the PPAR co-activator, PGC1? in both liver and skeletal muscle. Histology and blood chemistry analysis indicated this route of administration was not associated with damage to the intestine, kidney, or liver. These results suggest that the complexation of naringenin with HP?CD is a viable option for the oral delivery of naringenin as a therapeutic entity with applications in the treatment of dyslipidemia, diabetes, and HCV infection.

| S-EPMC3071816 | biostudies-literature

Investigation of Praziquantel/Cyclodextrin Inclusion Complexation by NMR and LC-HRMS/MS: Mechanism, Solubility, Chemical Stability, and Degradation Products.

Project description:Praziquantel (PZQ) is a biopharmaceutical classification system (BCS) class II anthelmintic drug characterized by poor solubility and a bitter taste, both of which can be addressed by inclusion complexation with cyclodextrins (CD). In this work, a comprehensive investigation of praziquantel/cyclodextrin (PZQ/CD) complexes was conducted by means of UV-vis spectroscopy, spectrofluorimetry, NMR spectroscopy, liquid chromatography-high-resolution mass spectrometry (LC-HRMS/MS), and molecular modeling. Phase solubility studies revealed that among four CDs tested, the randomly methylated β-CD (RMβCD) and the sulfobutylether sodium salt β-CD (SBEβCD) resulted in the highest increase in PZQ solubility (approximately 16-fold). The formation of 1:1 inclusion complexes was confirmed by HRMS, NMR, and molecular modeling. Both cyclohexane and the central pyrazino ring, as well as an aromatic part of PZQ are included in the CD central cavity through several different binding modes, which exist simultaneously. Furthermore, the influence of CDs on PZQ stability was investigated in solution (HCl, NaOH, H2O2) and in the solid state (accelerated degradation, photostability) by ultra-high-performance liquid chromatography-diode array detection-tandem mass spectrometry (UPLC-DAD/MS). CD complexation promoted new degradation pathways of the drug. In addition to three already known PZQ degradants, seven new degradation products were identified (m/z 148, 215, 217, 301, 327, 343, and 378) and their structures were proposed based on HRMS/MS data. Solid complexes were prepared by mechanochemical activation, a solvent-free and ecologically acceptable method.

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Inclusion Complexation between α-Cyclodextrin and Oligo(ethylene glycol) Methyl Ether Methacrylate.

Project description:The preparation of inclusion complexes based on α-cyclodextrin (α-CD) and oligo(ethylene glycol) methyl ether methacrylate (OEGMA) was investigated aiming to reveal complexation particularities and thermodynamic and kinetic aspects as a function of the oligomer architecture. Small-angle X-ray scattering and isothermal titration calorimetry measurements revealed that oligomer molecular weight controls both the kinetics and thermodynamics of inclusion. Unlike linear ethylene glycol polymers, OEGMA groups possess a methacrylate group, which seems to act as a stopper, affecting their mode of complexation. Nuclear magnetic resonance spectra and relaxation measurements support the fact that methacrylate groups lie outside the α-CD ring and that a full sequential complexation of the oligomer ethylene oxide groups is not observed. These results allied to the temperature sensitivity of these oligomers and enable possible routes for chemical modifications and design of new stimuli-responsive materials.

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Advancing insights on β-cyclodextrin inclusion complexes with SSRIs through lens of X-ray diffraction and DFT calculation.

Project description:Depression-the global crisis hastened by the coronavirus outbreak, can be efficaciously treated by the selective serotonin reuptake inhibitors (SSRIs). Cyclodextrin (CD) inclusion complexation is a method of choice for reducing side effects and improving bioavailability of drugs. Here, we investigate in-depth the β-CD encapsulation of sertraline (STL) HCl (1) and fluoxetine (FXT) HCl (2) by single-crystal X-ray diffraction and DFT complete-geometry optimization, in comparison to the reported complex of paroxetine (PXT) base. X-ray analysis unveiled the 2:2 β-CD-STL/FXT complexes with two drug molecules inserting their halogen-containing aromatic ring in the β-CD dimeric cavity, which are stabilized by the interplay of intermolecular O2-H⋯N1-H⋯O3 H-bonds, C3/C5-H⋯π and halogen⋯halogen interactions. Similarly, the 1:1 β-CD-tricyclic-antidepressant (TCA) complexes have an exclusive inclusion mode of the aromatic ring, which is maintained by C3/C5-H⋯π interactions. By contrast, the 2:1 β-CD-PXT complex has a total inclusion that is stabilized by host-guest O6-H⋯N1-H⋯O5 H-bonds and C3-H⋯π interactions. The inherent stabilization energies of 1 and 2 evaluated using DFT calculation suggested that the improved thermodynamic stabilities via CD encapsulation facilitates the reduction of drug side effects. Moreover, the SSRI conformational flexibilities are thoroughly discussed for understanding of their pharmacoactivity.

| S-EPMC8450047 | biostudies-literature

Electrospun crosslinked poly-cyclodextrin nanofibers: Highly efficient molecular filtration thru host-guest inclusion complexation.

Project description:Water pollution is a serious concern for public health and environment in today's world; hence, there exists a strong demand to develop cost-effective, sustainable and eco-friendly membranes. Here, we produce a highly efficient molecular filter membrane based on bio-renewable material; cyclic oligosaccaharides known as cyclodextrins (CD). Crosslinked insoluble poly-CD nanofibers are produced by using electrospinning technique in the absence of any additional polymeric carrier. Poly-CD nanofibrous membrane exhibit significant affinity to a common class of organic pollutant (i.e. methylene blue (MB)). Remarkably, the electrospun poly-CD nanofibrous web can outdistance the commonly used filter material (i.e. activated carbon) in terms of removal capacity. The flexible and free-standing poly-CD nanofibrous membrane depicted outstanding filtration performance. We estimate of above 90% removal efficiency for highly concentrated solutions of MB pollutant (40?mg/L) under extremely high flux (3840 Lm-2h-1). Essentially, these poly-CD nanofibrous webs demonstrate quite rapid uptake of MB from liquid environment. Overall, bio-based flexible electrospun poly-CD nanofibrous membrane represents a highly efficient molecular filter for wastewater treatment.

| S-EPMC5547107 | biostudies-other

Dispersion corrected DFT approaches for anharmonic vibrational frequency calculations: nucleobases and their dimers.

Project description:Computational spectroscopy techniques have become in the last few years an effective means to analyze and assign infrared (IR) spectra of molecular systems of increasing dimensions and in different environments. However, transition from compilation of harmonic data to fully anharmonic simulations of spectra is still underway. The most promising results for large systems have been obtained, in our opinion, by perturbative vibrational approaches based on potential energy surfaces computed by hybrid (especially B3LYP) density functionals and medium size (e.g. SNSD) basis sets. In this framework, we are actively developing a comprehensive and robust computational protocol aimed at quantitative reproduction of the spectra of nucleic acid base complexes and their adsorption on solid supports (organic/inorganic). In this contribution we report the essential results of the first step devoted to isolated monomers and dimers. It is well known that in order to model the vibrational spectra of weakly bound molecular complexes dispersion interactions should be taken into proper account. In this work we have chosen two popular and inexpensive approaches to model dispersion interactions, namely the semi-empirical dispersion correction (D3) and pseudopotential based (DCP) methodologies both in conjunction with the B3LYP functional. These have been used for simulating fully anharmonic IR spectra of nucleobases and their dimers through generalized second order vibrational perturbation theory (GVPT2). We have studied, in particular, isolated adenine, hypoxanthine, uracil, thymine and cytosine, the hydrogen-bonded and stacked adenine and uracil dimers, and the stacked adenine-naphthalene heterodimer. Anharmonic frequencies are compared with standard B3LYP results and experimental findings, while the computed interaction energies and structures of complexes are compared to the best available theoretical estimates.

| S-EPMC4612423 | biostudies-literature

Stability of the Inclusion Complexes of Dodecanoic Acid with α-Cyclodextrin, β-Cyclodextrin and 2-HP-β-Cyclodextrin.

Project description:In the presented work, the stability of the formation of inclusion complexes of dodecanoic acid (lauric acid) with three cyclodextrins, α-cyclodextrin, β-cyclodextrin and 2-HP-β-cyclodextrin, was analyzed from the point of view of the size of the cavity in cyclodextrins, their molar mass and the structure of the studied fatty acid. The measurements were made in a wide temperature range of 283.15-318.15K. The conductometric method was used for these studies. The results obtained allowed us to determine the value of the theoretical limiting molar conductivity (Λm0) of the studied complexes, the values of the inclusion complex formation constants (Kf) and the values of thermodynamic functions (ΔG0, ΔH0 and ΔS0) describing the complexation process in the studied temperature range.

| S-EPMC10095696 | biostudies-literature

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