NL2036964A - Chiral amino acid-based deep eutectic solvents and their preparation method and application - Google Patents
Chiral amino acid-based deep eutectic solvents and their preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/44—Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/18—Polyhydroxylic acyclic alcohols
- C07C31/22—Trihydroxylic alcohols, e.g. glycerol
- C07C31/225—Glycerol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
- C07C59/08—Lactic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44704—Details; Accessories
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44704—Details; Accessories
- G01N27/44717—Arrangements for investigating the separated zones, e.g. localising zones
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44756—Apparatus specially adapted therefor
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Abstract
This invention relates to the pharmaceutical technology field and specifically involves chiral amino acid-based deep eutectic solvents (AADESs) along with their preparation 5 method and application. The specific technical solution includes the preparation method for chiral amino acid-based deep eutectic solvents. The method involves heating and stirring amino acid and a hydrogen bond donor in an oil bath until transparent. The hydrogen bond donor can be L-lactic acid or glycerol. The invention synthesizes novel deep eutectic solvents (DESS) based on chiral amino acids, which are characterized and 10 then used as chiral additives for enantiomeric separation in capillary electrophoresis (CE). The proposed AADESs/MD synergistic system significantly improves the enantiomeric separation of model drugs compared to the single MD system.
Description
Chiral amino acid-based deep eutectic solvents and their preparation method and application
The present invention relates to chiral amino acid-based deep eutectic solvents and their preparation method and application.
In the pharmaceutical field, the significance of chirality cannot be ignored. Many drugs are chiral compounds, and different enantiomers of these compounds may have a significant impact on biological activity, metabolism, and excretion, potentially leading to adverse reactions. Therefore, controlling the chirality of drugs is crucial in the drug development process.
Capillary electrophoresis (CE) is an efficient and cost-effective separation technique that can be effectively used for chiral analysis. By selecting appropriate chiral selectors, CE can achieve efficient separation and quantitative analysis of chiral compounds with different electrophoretic mobilities. Many compounds have been successfully developed as chiral selectors, including cyclodextrins and their derivatives, proteins, carbohydrates, crown ethers, antibiotics, and surfactants. Among them, carbohydrates, constitute a large family of chiral selectors with strong enantioselectivity in chiral separation.
Maltodextrin (MD) is a cyclic polysaccharide composed of several glucose molecules linked by a(1-4) glycosidic bonds. It can form a long-chain structure with a helical arrangement in aqueous solutions, exhibiting hydrophilicity on the outer wall and hydrophobicity in the inner cavity. Therefore, MD can adsorb and encapsulate other drug molecules, showing chiral selectivity for racemates. However, in many cases, the use of
MD alone may not achieve satisfactory separation results.
Deep eutectic solvents (DESs) are mixtures composed of hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs) in eutectic proportions. The strong interactions between components in DESs, such as hydrogen bonding, Lewis acid-base interactions, van der Waals forces, etc., further reduce their melting points compared to individual components. Moreover, as analogs of ionic liquids (ILs), DESs possess advantages such as thermal stability, flame retardancy, high ionic conductivity, and low vapor pressure. Compared to ILs, DESs are more environmentally friendly with easier access to raw materials and simpler preparation methods. Therefore, DESs have gained increasing attention from researchers. It is well-known that ILs have demonstrated enhanced effects on chiral separation in CE. Amino acid ionic liquids (AAILs) are widely used in chiral CE, including as buffer solution additives and chiral ligands.
Amino acids are excellent raw materials for preparing deep eutectic solvents. However, in existing studies, most of the investigated HBDs in DESs consist of polyols, carboxylic acids, and amines, while HBAs are mainly choline chloride or quaternary ammonium salts. Although the synergistic effect of DESs with traditional selectors (especially cyclodextrins and their derivatives) has been confirmed, research on chiral amino acid- based deep eutectic solvents (AADESs) in chiral CE has not been reported, leaving a significant research gap.
To address the shortcomings in the existing technology, the present invention provides chiral amino acid-based deep eutectic solvents and their preparation method and application.
In order to achieve the above objectives, the present invention is implemented through the following technical solutions:
The invention discloses a preparation method for chiral amino acid-based deep eutectic solvents, wherein amino acid and a hydrogen bond donor are heated and stirred in an oil bath until transparent, and the hydrogen bond donor is L-lactic acid or glycerol.
Preferably, the amino acid is L-valine or L-leucine.
Preferably, the molar ratio of amino acid to hydrogen bond donor is 1:2 to 1:6.
Preferably, the oil bath temperature is between 50°C and 100°C.
Correspondingly, the chiral amino acid-based deep eutectic solvents obtained by the above preparation method.
Correspondingly, the application of the chiral amino acid-based deep eutectic solvents obtained by the above preparation method in chiral separation in capillary electrophoresis.
Preferably, the chiral amino acid-based deep eutectic solvents are used as enantiomeric separation additives in capillary electrophoresis.
Preferably, the chiral amino acid-based deep eutectic solvents are used in conjunction with MD, with a concentration of 2.66%-4.66% (m/v) for MD and a concentration of 0.16%-0.66% (m/v) for the chiral amino acid-based deep eutectic solvents.
The present invention has the following beneficial effects:
The invention synthesizes novel DESs based on chiral amino acids, characterizes them, and uses them as enantiomeric separation additives in CE. The proposed AADESs/MD synergistic system significantly improves the enantiomeric separation of model drugs compared to the single MD system. The results indicate that AADESs can influence the inclusion effects between MD and enantiomers, making their interaction more intimate, further enhancing chiral separation. AADESs are proven to be excellent materials for chiral separation with broad application prospects.
The invention uses L-valine or L-leucine as hydrogen bond acceptors (HBAs), glycerol, and L-lactic acid as hydrogen bond donors (HBDs) to synthesize four types of AADESs.
Subsequently, these AADESs are used as additives added to the running buffer, forming a synergistic system with MD for chiral separation of four chiral model drugs, including doxapram (DOX), nefopam (NEF), citalopram (CIT), and ketoconazole (KET). The applicability of AADESs as buffer additives in CE chiral separation is studied, and the mechanism of action of AADESs in the synergistic separation system is further investigated.
Figure 1 shows the chemical structures of maltodextrin (A), the prepared amino acid deep eutectic solvents components (B) and four model drugs (C);
Figure 2 shows the 'H NMR spectra of four AADESs (500 MHz, heavy water); A, L- leucine-glycerol (LEU-GLY);, B, L-leucine-L-lactic acid (LEU-LAC), C, L-valine- glycerol (VAL-GLY); D, L-valine-L-lactic acid (VAL-LAC);
Figure 3 shows the FT-IR pattern of VAL-LAC DES and its components (L-valine and
L-lactic acid),
Figure 4 shows the effect of MD concentration on enantiomeric separation; conditions: capillary temperature, 25°C; separation voltage, 16kV; background electrolyte (BGE), 50mM Tris/H;PO4 buffer containing 0.5% VAL-GLY DESs and 2.66%-4.66% maltodextrin (m/v) ; the buffer pH, 3.0;
Figure 5 shows the effect of buffer pH on enantiomeric separation; conditions: capillary temperature, 25°C; separation voltage, 16kV; background electrolyte (BGE), SOmM
Tris/HsPO4 buffer containing 0.5% VAL-GLY DESs and 4.0% maltodextrin (m/v) the buffer pH, 2.5-3.2;
Figure 6 shows the effect of separation voltage on enantiomeric separation; conditions: capillary temperature,25°C; separation voltage, 14-20kV; background electrolyte (BGE) 50mM Tris/H;PO4 buffer containing 0.5% VAL-GLY DESs and 4.0% maltodextrin (m/v); the buffer pH, 3.0;
Figure 7 shows typical enantiomeric separation electropherogram in different systems; (1) LEU-GLY/MD system; (2) VAL-GLY/MD system; (3) LEU-LAC/MD system; (4)
VAL-LAC/MD system; (5) Single MD system. Conditions: capillary temperature, 25°C; separation voltage, 16kV; background electrolyte (BGE), 50mM Tns/H3PO, buffer containing 0.5% AADESs and 4.0% maltodextrin (m/v); buffer pH, 3.0;
Figure 8 (A) shows Effect of different MD concentrations on the separation of CIT enantiomers; (1-6 respectively represent concentrations of 0.66%, 1.33%, 2.0%, 2.66%, 3.33%, 4.0%, m/v); (B) shows double reciprocal method was used to calculate the binding constant; conditions were: capillary temperature, 25°C; separation voltage,
16kV; background electrolyte (BGE), 50mM Tris/H3PO: buffer containing 0.5% VAL-
GLY DESs and 0.66%-4.0% maltodextrin (m/v) ; buffer pH, 3.0;
Figure 9 shows the molecular simulation conformation of CIT enantiomers; (A) side view and vertical view (orthogonal and perspective) of MD, (B) separation of CIT 5 enantiomers in a single MD system, (C) separation of CIT enantiomers in VAL-
GLY/MD system. Hydrogen bonds are marked with green lines, 2 interactions are marked with orange lines, C atoms are gray, H atoms are white, O atoms are red, N atoms are dark blue, and F atoms are light blue.
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, rather than all the embodiments.
Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.
Unless otherwise specified, the technical means used in the implementation examples are conventional means well known to those skilled in the art.
Example 1
The present invention discloses a preparation method for chiral amino acid-based deep eutectic solvents. Amino acid and a hydrogen bond donor are mixed and heated in an oil bath at 50 to 100°C (preferably 80°C), with continuous stirring, until a uniform and transparent solution is obtained. The hydrogen bond donor is L-lactic acid or glycerol.
The amino acid used is L-valine or L-leucine. The molar ratio of amino acid to hydrogen bond donor is 1:2 to 1:6 (preferably 1:5). Finally, the obtained products are characterized using Nuclear Magnetic Resonance (NMR) and Fourier Transform Infrared
Spectroscopy (FT-IR) techniques.
Using the above method, the invention synthesizes four types of AADESs, including L- valine-glycerol (VAL-GLY, DESI), valine-L-lactic acid (VAL-LAC, DES2), L- leucine-glycerol (LEU-GLY, DES3), and L-leucine-L-lactic acid (LEU-LAC, DES4).
The characterization of the amino acid-based deep eutectic solvents prepared is presented below.
Figure 2 shows the !H NMR spectra of several AADESs, where proton peaks for each component are observed except for active hydrogen. This result indicates that the synthesis of AADESs does not involve proton rearrangement, and no new protons at different positions are generated.
Figure 3 displays the FT-IR spectra of VAL-LAC DES and its components (L-valine and L-lactic acid). As shown, the strong and broad stretching vibration peak of hydroxyl groups (vO-H) shifts from 3393 cm’! in L-lactic acid to 3385 cm’! in the formed DES.
The stretching vibration peak of methyl groups (vCHs, 2989 cm™) in L-lactic acid moves to 2985 cm’! in VAL-LAC. The characteristic peak (bending vibration, 8CHs) shifts from 1457 em in L-lactic acid to 1462 cm’! in the formed DES. The characteristic peak (1729 cm) in L-lactic acid attributed to carbonyl groups (vC=0) shifts to 1732 cm in
VAL-LAC. Additionally, the symmetric stretching vibration peak of methyl groups (vsCHs) shifts from 2953 em’? in L-leucine to 2985 cm™ in the product. The asymmetric stretching vibration peak of methyl groups (vasCHs) at 2629 cm’! in L-leucine changes to 2632 cm’? in the DES. All the observed results confirm the successful synthesis of
AADESs.
Example 2 1. Molecular Simulation Model Establishment and Optimization: The 3D structures of
MD (maltodextrin, dextrose equivalents 4.0-7.0), AADESs, and model drugs were constructed using ChemBioDraw Ultra 14.0 software. Based on the average molecular weight, the number of glucose units in MD was set to 15. The structures and energy optimization of these models were completed using ChemBio3D Ultra 14.0 software, and they were saved in pdb format for further molecular simulation. AutoDock employs an energy-based docking method to predict and calculate the affinity and binding free energy between molecules to find the optimal ligand-receptor binding mode. The workflow of AutoDock includes the following steps: preparation of receptor and ligand structure files, definition of the grid box (50Âx50Âx50Â in this study), exploration of feasible ligand conformations, calculation of interaction energy, result analysis, and visualization. The present invention utilized Discovery Studio 2.5 software to assist in analyzing simulation results. 2. Calculation of electrophoretic mobility and binding constants: Assuming a 1:1 inclusion relationship between enantiomers and MD, the electrophoretic mobility and binding constants can be calculated as follows. pu=LxD/A(Vxt) (1) w=(LA)/(Vxt) (2) (uepi)= UA (upd) K [CTH D(pepe) (3) w=un/mo=ulo/T (4)
In the above-described method, V represents the separation voltage (V), tr and ti represent the migration times of enantiomers without MD and with MD, respectively (s); L and | represent the total capillary length and effective capillary length, respectively (cm); HÉ Lr, wi, and pe represent the electrophoretic mobilities of free analyte, enantiomer, and enantiomer-MD complex, respectively; [C] represents the concentration of MD; K represents the binding constant between MD and enantiomer; n and To represent the viscosity of the buffer solution with and without MD, respectively; I and Io represent the current values with and without MD, respectively; u! and u represent the electrophoretic mobilities with and without correction.
As the viscosity of the buffer solution in CE experiments may change due to the increased concentration of MD, the electrophoretic mobility values may be affected.
Therefore, it is necessary to calibrate the electrophoretic mobility values. The present invention used current values to calibrate electrophoretic mobility. 3. Electrophoresis Conditions: The chiral separation experiment was conducted on a
CL 1030 electrophoresis system (Beijing Huayang Limin Instrument Co., Ltd., Beijing,
China) equipped with a power supply, UV absorption detector, and data recorder. The uncoated silica capillary was purchased from Yongnian Optical Fiber Factory (Hebei,
China), with a total length of 50 cm (effective length 40.5 cm) and an inner diameter of 50 um (outer diameter 365 um). The activation of a new capillary was performed by rinsing with 1M NaOH solution, 0.1M NaOH solution, and distilled water for 20 minutes each. Before each sample injection, the capillary was rinsed with 0.1M NaOH solution, distilled water, and running buffer for 3 minutes each. All samples were introduced into the capillary by siphoning (10 cm, 15 s) and monitored at different wavelengths (220 nm for NEF and DOX, 230 nm for KET, 245 nm for CIT). The capillary was thermostated at 25°C, and the separation voltage was set at 16 kV.
The racemic drugs were dissolved in a mixed solvent (methanol/water, volume ratio 1:1) to prepare a sample solution (0.5 mg/mL). Thiourea was used as a neutral marker to calculate the electroosmotic flow (EOF). The buffer solution was a 50 mM Tris solution containing a certain amount of AADESs and maltodextrin. After preparing the fresh running buffer, adjust the pH to the desired value. Before use, both the buffer solution and sample solution were filtered through a microporous membrane filter (0.45 um) and degassed by ultrasonication.
The chemical structures of maltodextrin (A), the components of the four AADESs prepared in the present invention (B), and the four racemic drugs (or four model drugs) (C) are shown in Figure 1.
Example 3
Optimization of Electrophoresis Conditions 1. In order to achieve better separation, VAL-GLY/MD was used as a model system for condition optimization. The effect of MD concentration in the range of 2.66% to 4.66% (m/v) on enantiomeric separation was studied (as shown in Figure 4). In chiral separation, MD forms stable complexes with the target compounds through non- covalent interactions. When the MD concentration is below 4.0% (m/v), the resolution (Rs) of the model drugs is positively correlated with the MD concentration. As the MD concentration continues to increase, Rs starts to decrease to varying degrees. Therefore, 4.0% (m/v) MD concentration was chosen for further analysis.
2. The concentration of DES has a significant impact on chiral separation (Table 1). In the range of 0-0.66% (m/v), the Rs values of model drugs first increase and then decrease. At a concentration of 0.5% (m/v), the Rs value reaches the maximum, indicating strong selectivity under this condition. Therefore, 0.5% (m/v) is considered the optimal DES concentration.
Table 1 Effect of DES concentration on enantiomeric separation
Concentration | 0 0.33% tt tt
Analyte t/t2(min) | Rs Rs Rs (min) (min) 10.049/ 11.367/ 13.822/
KET 171 | 1.03 2.11 | 1.038 2.74 | 1.047 10.350 11.796 14.473 10.148/ 12.765/
NEF 9.694/9.924 | LB | 1.024 13 | 1028 1.52 | 1.032 10.433 13.175 11.526/ 13.224/ 15.432/
CIT 182 | 1.039 236 | 1.043 3.04 | 1.054 11.976 13.821 16.263 141 13.330/ 16.015/
DOX 122 | 1.019 1.46 L67 | 1.027 11.628 13.621 16.448 15.809/ 18.210/
KET 1.055 3.12 | 1.056 16.681 19.229 14.000/ 15.863/
NEF 1.64 1.58 | 1.031 14.478 16.353 16.788/ 18.151/
CIT 3.34 | 1.06 3.25 | 1.063 17.788 19.296 18.159/ 19.797/
DOX 1.88 | 1.029 174 | 1.026 18.693 20.313
Conditions: Capillary temperature, 25°C; separation voltage, 16 kV; background electrolyte (BGE), 50 mM Tris/H;POy4 buffer containing 0-0.66% VAL-GLY DESs and 4.0% maltodextrin (m/v) ; buffer pH, 3.0. 3. The pH of the buffer solution has a significant impact on chiral CE separation. It can adjust the charge properties of analytes and the inner wall of the capillary, thereby affecting separation efficiency. This invention studied the influence of buffer pH in the range of 2.5-3.2 on chiral separation. These four model drugs are basic substances, and based on their pKa values, they carry positive charges in this pH range. As shown in
Figure 5, optimal separation was achieved at pH 3.0. Therefore, pH 3.0 was chosen as the optimal condition. 4. In chiral CE, an appropriate separation voltage can improve separation efficiency and shorten analysis time, allowing chiral compounds to separate better and faster. However, excessively high or low voltage can lead to poor separation efficiency. At lower voltages, extended migration times lead to peak broadening and reduced separation efficiency. At higher voltages, there is not enough opportunity for sufficient interaction between enantiomers and chiral reagents despite shorter migration times. After study, 16 kV was selected as the optimal separation voltage (as shown in Figure 6).
Example 4 Establishment of AADESs/MD Synergistic System
After optimizing the key parameters mentioned above, the system was used to separate four racemic drugs. The results in Figure 7 show significant improvement in the separation of all model drugs in the four synergistic separation systems compared to the single MD system. NEF and DOX could not achieve baseline separation in the single
MD system but were completely separated in the four synergistic systems. These observations indicate that the prepared AADESs and MD have a good synergistic effect on enantiomeric separation, making AADESs a class of materials with promising applications.
We note that the migration times of model drugs in several synergistic systems have been extended. DES exhibits some characteristics of ionic liquids and can also inhibit capillary electroosmotic flow. The proposed AADESs may directly interact with chiral compounds in the buffer solution, which also increases the migration time of drugs. In addition, the addition of DES can increase the viscosity of the buffer solution. These reasons lead to longer analysis times. However, appropriately extending migration time is beneficial for separation. For the four different AADESs, the separation of model drugs in their respective systems is also different. Overall, the VAL-GLY/MD and LEU-
GLY/MD systems exhibit stronger enantiomeric selectivity, while the VAL-LAC/MD system has relatively poorer selectivity. The separation results are directly related to the structure of AADESs, indicating that AADESs are involved in the chiral recognition process.
Example 5 Calculation of Binding Constants
Binding constants are important parameters that characterize the strength of molecular interactions between receptors and ligands. In chiral CE, binding constants also indicate the selectivity of chiral selectors for enantiomers. The binding constants were calculated using the double reciprocal plot method.
The separation of CIT enantiomers in the single MD system and the VAL-GLY/MD system was studied within the MD concentration range of 0.66%-4.0% (m/v) (Figure 8), and the electrophoretic mobility under different conditions was calculated (Table 2). By performing linear regression on the data in Table 2, with 1/[CD] as the independent variable and 1/(uf-pi) as the dependent variable, linear regression equations were obtained. The ratio of the intercept to the slope of the equation is the desired binding constant. In the single MD system, the binding constants between MD and R-CIT, S-
CIT enantiomers were 4.70 and 5.47 mL/g, respectively (A=0.77). However, in the
VAL-GLY/MD system, the binding constants between MD and R-CIT, S-CIT enantiomers were 11.55 and 12.80 mL/g, respectively (A=1.25). In the presence of
AADESs, not only were the binding constants between MD and CIT enantiomers larger, but the difference between the two enantiomers also increased significantly, from 0.77 to 1.25. The significant enhancement of binding constants is responsible for the improvement in chiral separation.
Table 2 Corrected electrophoretic mobility of CIT enantiomers ee
Concentration (g/mL) 0.020 0.026 0.032
Example 6 Mechanism Study of AADESs Using Molecular Simulation
Conditions: Capillary temperature, 25°C; separation voltage, 16 kV; background electrolyte (BGE), 50 mM Tris/H;PO4 buffer containing 0.5% VAL-GLY DESs and 0.66%-4.0% maltodextrin (m/v) ; Buffer pH, 3.0.
AutoDock utilizes algorithms to explore the conformational space of the binding sites between ligands (enantiomers) and receptors (chiral selectors). The present invention used AutoDock 4.2.3 to study specific chiral recognition mechanisms. The docking results for the four model drugs in the single MD system and the four synergistic systems are summarized in Table 3.
Binding free energy (AG) can be used to predict the direction and likelihood of chemical changes under isothermal and isobaric conditions. A positive AG reflects an unstable system that requires external input of energy for a chemical reaction to occur. A negative value indicates a stable system capable of undergoing a spontaneous chemical reaction releasing energy. Generally, a larger negative value represents a more stable complex, i.e. a more spontaneous reaction.
As shown in Table 3, all AG values are negative, indicating the spontaneous inclusion of enantiomers by MD. The absolute values of AG in the four synergistic systems are significantly increased compared to the single MD system. This observation aligns with the improvement in electrophoretic separation results. Additionally, the absolute difference in AG (|JAAG]) between R and S enantiomers was calculated, representing another important parameter in thermodynamics reflecting enantioselectivity. In general, a higher numerical value indicates a stronger enantioselectivity in the system.
The simulation results also demonstrate good consistency with the separation results.
Table 3 Binding free energies of enantiomers and maltodextrin in different systems
AG | AG | |JAAG| | AG | AG | AAG] | AG | AG | AAG] | AG | AG | [AAG]
System
Rr! 8? 12 pl! $2 12 rl $2 1,2 ri s 12
Single | - - - - - - - 0.35 49 | 0,12 0.32 0.23
MD 6.22 | 6.57 4.78 511 | 543 401 | 3.78
VAL-
LAC/M 0.48 0.23 0.44 0.31 7.15 | 7.63 6.01 | 6.24 564 | 6.08 426 | 3.95
D
VAL-
GLY/ 82 1054 -6.7 | 0.37 0.4 7.66 6.33 588 | 6.41 4.24
MD
LEU-
LAC/M 0.56 0.26 0.48 0.36 8.01 | 8.57 6.05 | 6.31 561 | 6.09 3.99
D
LEU-
GLY/ 87 {0.72 034 | -59 0.52 0.38 7.98 6.34 | 6.68 6.42 443 | 4.05
MD
L The unit is kcal/mol; ? The absolute value of the difference in free binding energies between the (R)- and (S)-enantiomers. 2. AutoDock can provide a visual interface for the interaction between chiral selectors and enantiomers. Many interactions, such as hydrogen bonding, hydrophobic effects, electrostatic interactions, van der Waals forces, and steric repulsion, jointly determine the interaction mode between the chiral selector and the enantiomer, as well as the chiral recognition process.
Figure 9 presents the molecular simulation conformations of CIT enantiomers in the single MD system and the VAL-GLY/MD system. In the single MD molecular simulation system, only a few hydrogen bonds were observed (indicated by green lines), while in the VAL-GLY/MD system, the number of hydrogen bonds significantly increased. Some 2 interactions (indicated by orange lines), especially o-z interactions, were also detected in the synergistic system. Additionally, direct interactions between enantiomers and VAL-GLY DES were observed, confirming the involvement of
AADESs in the chiral recognition process. All these observations indicate an enhanced affinity between CIT enantiomers and the chiral reagent, leading to an improved chiral separation effect.
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