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

Abstract

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.

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

“…For the past five years, we have launched a series of comprehensive structural studies by single-crystal X-ray diffraction combined with density functional theory (DFT) calculation for the atomic-level understanding of the β-CD-antidepressant inclusion complexes. We have unambiguously unveiled the nature and characteristics of inclusion complexation of β-CD with TCAs [30][31][32][33] and SSRIs [34]. Although TCAs and SSRIs do not share structural similarities, and they complex with β-CD at different host-guest ratios, their inclusion structures are in common with the aromatic ring embedded in the CD cavity and are similarly stabilized by C-H•••π interactions.…”

“…Conversely, the twofold disordered C63-O63-H are pointed inward to the β-CD cavity with χ, ω having opposite signs of −160.3° to −176.7°, 65.4-68.4° (Table S2). ) distances of the β-CD glucose units (G1-G7) depicting the host conformational changes upon inclusion of the halogen-containing antidepressants, clomipramine (CPM) HCl [32], PXT HCl (form II), PXT base (form I [35]) and fluoxetine (FXT) HCl [34], of which the averages of two similar β-CD monomers in the β-CD dimer are shown. For comparison, data of the inclusion complex of β-CD-(-)-epicatechin (EC) [42] and the uncomplexed β-CD•12H2O [40] are included; see also Table S2.…”

“…Although TCAs and SSRIs do not share structural similarities, and they complex with β-CD at different host-guest ratios, their inclusion structures are in common with the aromatic ring embedded in the CD cavity and are similarly stabilized by C-H•••π interactions. The presence of guest-guest halogen•••halogen interactions facilitate the 2:2 β-CD-sertraline/fluoxetine HCl inclusion complexation [34]. On the other hand, without intermolecular halogen•••halogen interactions, the β-CD-TCA HCl complexes exclusively exist in a unimolar ratio [30][31][32][33].…”

“…As the structural components are extended from 2-3 rings in sertraline/fluoxetine to 4 rings in PXT, the bulkier drug molecule adapts its structure to a unique U-shaped conformation for total inclusion in the β-CD dimeric cavity, yielding a 2:1 host-guest complex [35]. The improved thermodynamic stabilities of the β-CD-antidepressant complexes perceived by DFT calculations help to lessen side effects and enhance the bioavailability of drugs [33,34].…”

“…The larger root mean square (rms) fits (i.e., the greater structural differences) are obtained when comparing the drugs bound to proteins with those in other circumstances. This suggests that the pharmacological functions of drugs require conformational adaptability for optimal binding to target proteins [36], as demonstrated for TCAs (nortriptyline, amitriptyline, clomipramine and doxepin, [30,32] and SSRIs (sertraline, fluoxetine and PXT) [34].…”