A Comprehensive Investigation of Interactions between Antipsychotic Drug Quetiapine and Human Serum Albumin Using Multi-Spectroscopic, Biochemical, and Molecular Modeling Approaches (original) (raw)
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The interaction between perazine dimaleate (PDM) and bovine serum albumin (BSA) was investigated by voltammetry, fluorescence spectroscopy, UV-vis spectroscopy, molecular docking and viscometric methods. The study was carried out in acetate buffer solution of pH 7.2, which was prepared by using 0.1 M sodium acetate and adjusting pH using 0.1 M hydrochloric acid. The voltammetric study of PDM shows a pair of well redox peaks at 0.538 and 0.471 V (versus SCE) on a GCE in acetate buffer of pH 7.2 at 50 mV s-1. After the addition of BSA into the PDM solution, the redox peak currents decreased gradually, and peak potentials shifted towards negative direction. The results of voltammetry, fluorescence quenching and UV-vis absorption spectra experiments indicated the formation BSA-PDM complex. The binding parameters like binding constant and binding free energy were determined from voltammetric data. The binding constant and binding energy was also determined from UV-vis and fluorescence spectroscopy with a value quite close to that obtained from CV.
Molecules
The aim of this study was to analyze the binding interactions between a common antihypertensive drug (amlodipine besylate—AML) and the widely distributed plant flavonoid quercetin (Q), in the presence of human serum albumin (HSA). Fluorescence analysis was implemented to investigate the effect of ligands on albumin intrinsic fluorescence and to define the binding and quenching properties. Further methods, such as circular dichroism and FT-IR, were used to obtain more details. The data show that both of these compounds bind to Sudlow’s Site 1 on HSA and that there exists a competitive interaction between them. Q is able to displace AML from its binding site and the presence of AML makes it easier for Q to bind. AML binds with the lower affinity and if the binding site is already occupied by Q, it binds to the secondary binding site inside the same hydrophobic pocket of Sudlow’s Site 1, with exactly the same affinity. Experimental data were complemented with molecular docking studies....
Future Journal of Pharmaceutical Sciences
Background Multidrug regimens can increase the risk of drug–drug interactions at the level of albumin binding especially for drugs with narrow therapeutic windows such as carbamazepine (CBZ). This risk is particularly heightened for CBZ which is mainly metabolized to the active carbamazepine-10,11-epoxide (CBZE) that has been identified as contributory to both the therapeutic efficacy and severity of toxicity in CBZ-treated individuals. The objective of this study was to investigate the binding affinities of albumin with CBZ and CBZE, and to explore the influence of two competing over-the-counter medicines on the binding characteristics. CBZE was synthesized by epoxidation of CBZ and characterized using IR, NMR and mass spectrometry. The influence of paracetamol and ascorbic acid on the albumin complexes of CBZ and CBZE was investigated using absorption and IR spectrophotometry. Results Protein–ligand complexation produced progressive hyperchromic changes in 278 nm band of bovine se...
Herein we report the interaction of amphiphilic drug clomipramine hydrochloride (CLP-a tricyclic antidepressant) with bovine serum albumin (BSA) studied by fluorescence, UV-vis, and circular dichroism (CD) spectroscopic techniques. Clomipramine hydrochloride is used to treat a variety of mental health problems. The quenching rate constant (k q ) values, calculated according to the fluorescence data, decrease with increase in temperature indicating the static quenching procedure for the CLP-BSA interaction. The association binding constants (K A ), evaluated at different conditions, and the thermodynamic parameters (free energy, enthalpy and entropy changes) indicate that the hydrophobic forces play a major role in the binding interaction of drug. The interaction of BSA with CLP was further confirmed by UV absorption spectra. Blue shift of position was detected due to the complex formation between the BSA-CLP. The molecular distance, r 0 , between donor (BSA) and acceptor (CLP) was estimated by fluorescence resonance energy transfer (FRET) whose value (4.47 nm) suggests high probability of static quenching interaction. The CD results prove the conformational changes in the BSA on binding with the drug. Thus, the results supply qualitative and quantitative understanding of the binding of BSA to CLP, which is important in understanding their effect as therapeutic agents.
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The aim of this study was to analyze the binding interactions between a common antihypertensive drug (ramipril, R) and the widely distributed plant flavonoid quercetin (Q), in the presence of human serum albumin (HSA). From the observed fluorescence spectra of the (HSA + R) system we can assume that ramipril is also one of the Site 3 ligands—similar to fusidic acid—the binding of which has been proven by RTG crystallography. Our claim is supported by near-UV CD spectroscopy, microscale themophoresis and molecular modeling. The presence of R slightly inhibited the subsequent binding of Q to HSA and, on the contrary, the pre-incubation of HSA with Q caused a stronger binding of R, most likely due to allosteric interactions. At high concentrations, R is also able to displace Q from its binding site. The dissociation constant KD for the binding of R is more than hundredfold larger than for Q, which means that R is a very weak binder to HSA. The knowledge of qualitative and quantitative ...
Journal of Photochemistry and Photobiology B-biology, 2017
Lamotrigine (an epileptic drug) interaction with human serum albumin (HSA) was investigated by fluorescence, UV-Vis, FTIR, CD spectroscopic techniques, and molecular modeling methods. Binding constant (K b) of 5.7410 3 and number of binding site of 0.97 showed that there is a slight interaction between lamotrigine and HSA. Thermodynamic studies was constructed using the flourimetric titrations in three different temperatures and the resulted data used to calculate the parameters using Vant Hoff equation. Decreased Stern Volmer quenching constant by enhanced temperature revealed the static quenching mechanism. Negative standard enthalpy (H) and standard entropy (S) changes indicated that van der Waals interactions and hydrogen bonds were dominant forces which facilitate the binding of Lamotrigine to HSA, the results were confirmed by molecular docking studies which showed no hydrogen binding. The FRET studies showed that there is a possibility of energy transfer between Trp214 and lamotrigine. Also the binding of lamotrigine to HSA in the studied concentrations was not as much as many other drugs, but the secondary structure of the HSA was significantly changed following the interaction in a way that -helix percentage was reduced from 67% to 57% after the addition of lamotrigine in the molar ratio of 4:1 to HSA. According to the docking studies, lamotrigine binds to IB site preferably.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2019
Trifluoperazine is a potent antipsychotic drug used in the treatment of neurological disorders. The usage of trifluoperazine is often found to be associated with more adverse side effects as compared to other low-potency antipsychotic agents. Plasma proteins play an inevitable role in determining the pharmacokinetic properties of a drug. Hence, this study was conducted with an aim to characterize the interactions of trifluoperazine with bovine serum albumin and determine the influence of other small molecules on its interaction with serum albumin. Trifluoperazine bound to BSA at two independent sites with K d values of 9.5 and 172.6 mM. F€ orster resonance energy transfer and computational docking analysis revealed that both the binding sites of trifluoperazine were located closer to TRP 213 in subdomain IIA of BSA. Evaluation of trifluoperazine-BSA interactions at three different temperatures indicated that there was a stable complex formation between the two molecules at the ground state and that the static quenching mechanism was predominant behind these interactions. Binding studies in the presence of pharmaceutically relevant drugs indicated that warfarin, paracetamol, and caffeine negatively influenced the binding of trifluoperazine on BSA. Lastly, Fourier transformed infrared spectroscopy and circular dichroism spectroscopy indicated that the binding of trifluoperazine induced a conformational change by reducing the a-helical content of BSA. The study implicates that the small molecules which prefer binding to the Sudlow site I of BSA might compete with trifluoperazine for its binding site thereby increasing the concentration of free trifluoperazine in the plasma which could lead to adverse side effects in patients.
2009
The interest on phenothiazine drugs has been increased during last years due to their proved utility in the treatment of several diseases and biomolecular processes. In the present work, the binding of the amphiphilic phenothiazines promazine and thioridazine hydrochlorides to the carrier protein human serum albumin (HSA) has been examined by f-potential, isothermal titration calorimetry (ITC), fluorescence and circular dichorism (CD) spectroscopies, and dynamic light scattering (DLS) at physiological pH with the aim of analyzing the role of the different interactions in the drug complexation process with this protein. The f-potential results were used to check the existence of complexation. This is confirmed by a progressive screening of the protein charge up to a reversal point as a consequence of drug binding. On the other hand, binding causes alterations on the tertiary and secondary structures of the protein, which were observed by fluorescence and CD spectroscopies, involving a two-step, three-state transition. The thermodynamics of the binding process was derived from ITC results. The binding enthalpies were negative, which reveal the existence of electrostatic interactions between protein and drug molecules. In addition, increases in entropy are consistent with the predominance of hydrophobic interactions. Two different classes of binding sites were detected, viz. Binding to the first class of binding sites is dominated by an enthalpic contribution due to electrostatic interactions whereas binding to a second class of binding sites is dominated by hydrophobic bonding. In the light of these results, protein conformational change resembles the acid-induced denaturation of HSA with accumulation of an intermediate state.
The interaction between two proton pump inhibitors viz., omeprazole (OME) and esomeprazole (EPZ) with human serum albumin (HSA) was studied by fluorescence, absorption, circular dichroism (CD), Fourier transform infrared spectroscopy (FT-IR), voltammetry, and molecular modeling approaches. The Stern-Volmer quenching constants (K sv) for OME-HSA and EPZ-HSA systems obtained at different temperatures revealed that both OME and EPZ quenched the intensity of HSA through dynamic mode of quenching mechanism. The binding constants of OME-HSA and EPZ-HSA increased with temperature, indicating the increased stability of these systems at higher temperatures. Thermodynamic parameters viz., ΔH°, ΔS°, and ΔG°were determined for both systems. These values revealed that both systems were stabilized by hydrophobic forces. The competitive displacement and molecular docking studies suggested that OME/EPZ was bound to Sudlow's site I in subdomain IIA in HSA. The extent of energy transfer from HSA to OME/EPZ and the distance of separation in tryptophan (Trp214) Trp214-OME and Trp214-EPZ was determined based on the theory of fluorescence resonance energy transfer. UV absorption, 3D fluorescence, and CD studies indicated that the binding of OME/EPZ to HSA has induced micro environmental changes around the protein which resulted changes in its secondary structure.
Biomacromolecules, 2004
Interactions of two amphiphilic antidepressant drugs, imipramine and desipramine hydrochlorides, with the blood protein human serum albumin (HSA) were investigated to gain an understanding of the effects of drug molecular structure on the complex formation of drug-protein molecules. To elucidate the mechanisms of such effects, the protein-antidepressant interactions in aqueous buffered solutions of pH 3.0 and 5.5 (isoelectric point of HSA ) 4.9) were investigated using conductivity, potential, and dynamic light scattering. An increase of the critical micelle concentration of both antidepressants was detected as a consequence of extensive binding to the protein. From -potential measurements, the Gibbs energies of adsorption of the drugs onto the protein were derived using the proposed models of Kayes and Ottewill and Watanabe. Measurements of the hydrodynamic radii of HSA-antidepressant complexes as a function of the drug concentration have shown a gradual increase of size of a saturation rather than a denaturation process of the protein. A larger drug adsorption at pH 5.5 than at pH 3.0 was also observed, as a consequence of a more important specific binding at the former pH. Figure 4. Decay time distributions in the aqueous solution of HSA (0.125% w/v) and imipramine at pH 5.5 at concentrations of (a) 0.0075, (b) 0.018, (c) 0.033, (d) 0.055, (e) 0.070, and (f) 0.10 mol kg -1 .