Thermodynamic Studies of Interactions between Sertraline Hydrochloride and Randomly Methylated β-Cyclodextrin Molecules Supported by Circular Dichroism Spectroscopy and Molecular Docking Results

Abstract

The interaction between sertraline hydrochloride (SRT) and randomly methylated β-cyclodextrin (RMβCD) molecules have been investigated at 298.15 K under atmospheric pressure. The method used-Isothermal Titration Calorimetry (ITC) enabled to determine values of the thermodynamic functions like the enthalpy (ΔH), the entropy (ΔS) and the Gibbs free energy (ΔG) of binding for the examined system. Moreover, the stoichiometry coefficient of binding (n) and binding/association constant (K) value have been calculated from the experimental results. The obtained outcome was compared with the data from the literature for other non-ionic βCD derivatives interacting with SRT and the enthalpy-entropy compensation were observed and interpreted. Furthermore, the connection of RMβCD with SRT was characterized by circular dichroism spectroscopy (CD) and complexes of βCD derivatives with SRT were characterized through the computational studies with the use of molecular docking (MD).

Keywords: circular dichroism; isothermal titration calorimetry; methylated β-cyclodextrin; molecular docking; sertraline hydrochloride; β-cyclodextrin.

Figure 1

(a) Sertraline hydrochloride structural formula (on the left) and the models made based on crystal structure of sertraline hydrochloride (on the right) with refcode CAVVUQ [46] from the Cambridge Structural Database (CSD) [47] and (b) a general structural formula of some β-cyclodextrins (on the left) and crystal structure of RMβCD (on the right) with refcode JOSWOD [48] from the CSD [47].

Figure 2

The integrated thermal effects corresponding to the binding interaction during titration of a 0.45 mM sertraline hydrochloride solution (in a cell) with a 15 mM solution of randomly methylated-β-cyclodextrin (in a syringe) (■ navy blue) for aqueous solutions with pH ≈ 6.8 at 298.15 K under atmospheric pressure p = 101,800 Pa together with the effects of SRT (●gray) and RMβCD (■ cyan) dilution by pure water.

Figure 3

Binding free Gibbs energy (ΔG), enthalpy (ΔH), and entropy factor (TΔS) of inclusion complex formation between SRT and: βCD [41], DMβCD [41], HPβCD [42], RMβCD (this work).

Figure 4

The enthalpy-entropy compensation plot for inclusion complexes of sertraline hydrochloride molecules with chosen β-cyclodextrin molecules: βCD [41], DMβCD [41], HPβCD [42], RMβCD (this work). The determined coefficients of the linear equation TΔS = α∙ΔH + TΔS₀ [21] with R² = 0.99 are: α = (0.946 ± 0.068) kJ∙mol⁻¹ and TΔS₀ = (20.8 ± 1.1) kJ∙mol⁻¹.

Figure 5

The circular dichroism spectrum of 0.3 mM sertraline hydrochloride aqueous solution (red line) together with spectrum of the 0.3 mM randomly methylated-β-cyclodextrin aqueous solution (cyan line) and the spectra of drug-cyclodextrin mixtures (from black with ratio of 1:0.5 thru the ratio 1:1, 1:2 to light gray with ratio of 1:3 for SRT:RMβCD) with constant concentration of SRT and growing content of RMβCD to the maximum concentration of 10 mM (blue line with ratio of 1:33).

Figure 6

The change in circular dichroism intensity (ΔCD) of SRT at 274 nm as a function of RMβCD concentration. The red solid line represents the best fit of Equation (2) to the experimental results presented as the black points and the parameters from fitting calculations are placed in Table 2.

Figure 7

The geometry of the SRT-βCD complex with stoichiometry 1:3 (I-II-III or “head-to-head-to-tail” as in [69,70]) obtained by the Molecular Docking (MD) simulations with the use of βCD crystal structure with refcode 648855 [67] from The Cambridge Structural Database (CSD) [47].

Figure 8

The geometries of the SRT-βCD complex with stoichiometry 1:2 (I-II for (A) or “head-to-head” [69,70] and II-III or “head-to-tail” for (B) obtained by MD simulations with the use of βCD crystal structure with refcode 648855 [67] from the CSD database [47].

Figure 9

The geometries of the SRT-βCD complex with stoichiometry 1:1-I for (A), II for (B) and III for (C)-obtained by MD simulations with the use of βCD crystal structure with refcode 648855 [67] from the CSD database [47].

Figure 10

The geometries of the SRT-TMβCD complex with stoichiometry 1:2 (I-II or “head-to-head” [69,70]) obtained by MD simulations with the use of TMβCD crystal structure with refcode ALIGAE [68] from the CSD database [47].

Figure 11

The geometry of the SRT-TMβCD complex with stoichiometry 1:1 (I for (A) and II for (B) structure) obtained by MD simulations with the use of TMβCD crystal structure with refcode ALIGAE [68] from the CSD database [47].

Figure 12

The geometry of the SRT-RMβCD complex with stoichiometry 1:1 obtained by MD simulations with the use of RMβCD crystal structure with refcode JOSWOD [48] from the CSD database [47].