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Inclusion Scenarios and Conformational Flexibility of the SSRI Paroxetine as Perceived from Polymorphism of β-Cyclodextrin-Paroxetine Complex.

ABSTRACT: Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the β-cyclodextrin (β-CD)-SSRI inclusion complexes by X-ray crystallography combined with density functional theory (DFT) calculation. Here, we report a new crystal form (II) of the 1:1 β-CD-paroxetine (PXT) complex, which is inspired by the reported 2:1 β-CD-PXT complex (crystal form I), reflecting an elusive phenomenon of the polymorphism in CD inclusion complexes. The β-CD-PXT polymorphism stems from the PXT conformational flexibility, which is defined by torsion angles κ, ε around the -CH₂-O- group bridging the A- and C-D-rings, of which those of PXT in I and II are totally different. While PXT (II) in an open V-shaped conformation that has the B-ring shallowly inserted in the β-CD cavity, PXT (I) in a closed U-shaped structure is mostly entirely embedded in the β-CD dimeric cavity, of which the A-ring is deeply inserted in the main β-CD cavity. However, PXT molecules in both crystal forms are similarly maintained in the CD cavity via host-guest N-H···O5/O6 H-bonds and C/O-H···π(B/C) interactions and β-CDs have similar 3D arrangements, channel (II) vs. screw-channel (I). Further theoretical explorations on the β-CD-PXT thermodynamic stabilities and the PXT conformational stabilities based on their potential energy surfaces (PESs) have been completed by DFT calculations. The 2:1 β-CD-PXT complex with the greater presence of dispersion interactions is more energetically favorable than the unimolar complex. Conversely, whereas free PXT, PXT (II) and PXT in complex with serotonin transporter are more energetically stable, PXT (I) is least stable and stabilized in the β-CD cavity. As SSRIs could lessen the COVID-19 severity, the CD inclusion complexation not only helps to improve the drug bioavailability, but also promotes the use of antidepressants and COVID-19 medicines concurrently.

SUBMITTER: Aree T

PROVIDER: S-EPMC8781563 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn this study we investigated the predictability of three thermodynamic quantities related to complex formation. As a model system we chose the host-guest complexes of beta-cyclodextrin (beta-CD) with different guest molecules. A training dataset comprised of 176 beta-CD guest molecules with experimentally determined thermodynamic quantities was taken from the literature. We compared the performance of three different statistical regression methods - principal component regression (PCR), partial least squares regression (PLSR), and support vector machine regression combined with forward feature selection (SVMR/FSS) - with respect to their ability to generate predictive quantitative structure property relationship (QSPR) models for DeltaG degrees, DeltaH degrees and DeltaS degrees on the basis of computed molecular descriptors.ResultsWe found that SVMR/FFS marginally outperforms PLSR and PCR in the prediction of DeltaG degrees, with PLSR performing slightly better than PCR. PLSR and PCR proved to be more stable in a nested cross-validation protocol. Whereas DeltaG degrees can be predicted in good agreement with experimental values, none of the methods led to comparably good predictive models for DeltaH degrees. In using the methods outlined in this study, we found that DeltaS degrees appears almost unpredictable. In order to understand the differences in the ease of predicting the quantities, we performed a detailed analysis. As a result we can show that free energies are less sensitive (than enthalpy or entropy) to the small structural variations of guest molecules. This property, as well as the lower sensitivity of DeltaG degrees to experimental conditions, are possible explanations for its greater predictability.ConclusionThis study shows that the ease of predicting DeltaG degrees cannot be explained by the predictability of either DeltaH degrees or DeltaS degrees. Our analysis suggests that the poor predictability of TDeltaS degrees and, to a lesser extent, DeltaH degrees has to do with a stronger dependence of these quantities on the structural details of the complex and only to a lesser extent on experimental error.

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Inclusion Scenarios and Conformational Flexibility of the SSRI Paroxetine as Perceived from Polymorphism of β-Cyclodextrin-Paroxetine Complex.

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