Mechanistic insights into the interaction of anxiolytic drugs with human serum albumin in a ternary system utilizing spectroscopic and molecular modeling approaches.

In recent years, buspirone has been co-administered with sertraline to resolve sexual disorders caused by sertraline. Therefore, the present study was conducted to investigate the interaction effect of two antidepressants and anxiolytic drugs, sertraline and buspirone, on human serum albumin (HSA) using spectroscopic and molecular docking techniques. Fluorescence emission spectroscopy and molecular docking were used to calculate the binding affinity and determine the best binding sites for these two drugs. Additionally, UV-visible and circular dichroism spectroscopy were performed to investigate the effect of these drugs on the conformational changes of HSA. The results showed that both drugs have a strong ability to quench the fluorescence of HSA through a static mechanism, and cause structural changes in HSA. It was also found that binding of sertraline and buspirone to HSA is spontaneous (ΔG° <) and hydrophobic interactions, van der Waals forces and hydrogen bonds play a significant role in these interactions in the ternary system. In addition, molecular docking data showed that both drugs bind with high affinity to the Trp residue in subdomain IIA. The binding constants (Kb) for (HSA-SRH)-BSH and (HSA-BSH)-SRH were equal to 6.30 and 3.99, respectively, at 298 K. This study demonstrates that the presence of the second drug (buspirone/sertraline) affects the interaction and binding affinity of the first drug (sertraline/buspirone) to human serum albumin.

Central composite design-assisted visual and non-invasive detection of sertraline by sweet lemon waste-derived core-shell AuNPs@CDs.

This study reports a fast and visual detection method of antidepressant sertraline (SRT) drug by the core-shell AuNPs@CDs as the nanoprobes. The CDs has been eco-friendly synthesized from sweet lemon wastes to directly reduce Au+ to AuNPs without any external photoirradiation process or additional reductants. Optimizing key variables that impact the sensing process has been done using the central composite design (CCD) approach to simulate the assay condition before the analysis. Adding SRT with different concentrations to the nanoprobes under mildly acidic conditions presents an absorbance peak at 560 nm with purple color tonalities that differ from the behavior of alone nanoprobes (530 nm, pink color). The obtained absorption change is linearly proportional to the increase of SRT concentration from 1 µM to 35 µM with a limit of detection (LOD) value of 100 nM. The color changes with a vivid tonality from pink and purple to violet as the colorful fingerprint patterns are readily traceable by the naked eye, allowing the visual assay of SRT. The greenness of the developed approach is well evaluated by some international indexes including the complimentary green analytical procedure (ComplexGAPI) and also, the analytical greenness (AGREE) indexes. The proposed waste-derived nanoprobes based on the eco-friendly procedure not only conduct quantitative and qualitative non-invasive analysis of SRT by the naked eye but also, may widen for other applications in various fields.

Antidepressant Sertraline Hydrochloride Inhibits the Growth of HER2+ AU565 Breast Cancer Cell Line through Induction of Apoptosis and Cell Cycle Arrest.

BACKGROUND: Drug repurposing in oncology promises benefits to many patients through its ability to provide novel, and fast-tracked treatments. Previous studies have demonstrated that depression may influence tumor progression. Anti-proliferative activity of certain antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), are reported in the literature. OBJECTIVE: This study was conducted to repurpose selective serotonin reuptake inhibitors (SSRIs) for the treatment of breast cancers, and it merits further validation and research. METHODS: Changes in cell morphology were studied using DAPI staining, while the Annexin V/PI method was employed for apoptotic analysis. The expression of specific genes involved in cancer progression was also analyzed via RT-PCR. Caspase-3 activation was measured through fluorometric assay. RESULTS: We have identified that sertraline hydrochloride significantly inhibited the growth of breast cancer cell in vitro. Preliminary mechanistic studies demonstrated that the cytotoxicity of sertraline hydrochloride was possibly through the induction of apoptosis, as inferred from enhanced nuclear fragmentation, flow cytometric data, and caspase-3/7 activation. Gene expression analysis also showed an increased expression of pro-apoptotic Bax, and a slight decrease in oncogene c-myc in the presence of sertraline hydrochloride. CONCLUSION: In conclusion, our study suggest that sertraline hydrochloride, an antidepressant drug, can potentially be used for the treatment of breast cancer.

Revisiting the Molecular Interactions between the Tumor Protein TCTP and the Drugs Sertraline/Thioridazine.

TCTP protein is a pharmacological target in cancer and TCTP inhibitors such as sertraline have been evaluated in clinical trials. The direct interaction of TCTP with the drugs sertraline and thioridazine has been reported in vitro by SPR experiments to be in the ∼30-50 µM Kd range (Amson et al. Nature Med 2012), supporting a TCTP-dependent mode of action of the drugs on tumor cells. However, the molecular details of the interaction remain elusive although they are crucial to improve the efforts of on-going medicinal chemistry. In addition, TCTP can be phosphorylated by the Plk-1 kinase, which is indicative of poor prognosis in several cancers. The impact of phosphorylation on TCTP structure/dynamics and binding with therapeutical ligands remains unexplored. Here, we combined NMR, TSA, SPR, BLI and ITC techniques to probe the molecular interactions between TCTP with the drugs sertraline and thioridazine. We reveal that drug binding is much weaker than reported with an apparent ∼mM Kd and leads to protein destabilization that obscured the analysis of the published SPR data. We further demonstrate by NMR and SAXS that TCTP S46 phosphorylation does not promote tighter interaction between TCTP and sertraline. Accordingly, we question the supported model in which sertraline and thioridazine directly interact with isolated TCTP in tumor cells and discuss alternative modes of action for the drugs in light of current literature.

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

The interaction between sertraline hydrochloride (SRT) and randomly methylated ß-cyclodextrin (RMßCD) 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 ßCD derivatives interacting with SRT and the enthalpy-entropy compensation were observed and interpreted. Furthermore, the connection of RMßCD with SRT was characterized by circular dichroism spectroscopy (CD) and complexes of ßCD derivatives with SRT were characterized through the computational studies with the use of molecular docking (MD).

Fluoxetine and sertraline based multitarget inhibitors of cholinesterases and monoamine oxidase-A/B for the treatment of Alzheimer's disease: Synthesis, pharmacology and molecular modeling studies.

For the potential therapy of Alzheimer's disease (AD), cholinesterases (ChE) and monoamine oxidase (MAO) are key enzymes that regulate the level of acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) and monoamines. The aim of current research is the synthesis of multi-target compounds that can concomitantly inhibit ChEs and MAO. A series of fluoxetine and sertraline hybrids was designed and evaluated as multi-target inhibitors of ChEs and hMAO. In-vitro enzyme inhibition studies demonstrated that a number of compounds displayed excellent inhibition in submicromolar to nanomolar range. However, compounds 17, 22, 38-40 possess excellent concomitant inhibitory activity against ChEs and hMAO-A/B enzymes and thus emerged as optimal multi-target hybrids. In-vivo acute toxicity study showed the safety of synthesized compounds up to 2000 mg/kg dose. The examinations of brain tissue in Swiss albino mice suggested that selected most active MAO-B inhibitors 17 and 22 have a propensity to block the MAO-B activity that could be responsible for their neurodegenerative effect in mice. The in-vitro inhibitory manner of interaction of these multipotent compounds on all four targets were confirmed by molecular docking investigations.

Discovery of sertraline and its derivatives able to combat drug-resistant gastric cancer cell via inducing apoptosis.

Resistance phenomena during chemotherapy of tumor has been severely hampering the applications of chemotherapeutics. Due to advantage of drug repurposing, discovery of new chemosensitizers based on approved drugs is an effect strategy to find new candidates. Herein, we found antidepressant drug - sertraline, could sensitize drug-resistant gastric cancer cell (SGC-7901/DDP) with the IC50 value of 18.73 µM. To understand the structure-activity relationship and improve the activity, 30 derivatives were synthesized and evaluated. The IC50 value of the best compound was improved to 5.2 µM. Moreover, we found apoptosis induction and cell cycle arrest was the reason for the cell death of the drug-resistant cells after treatment of sertraline and derivatives, and PI3K/Akt/mTOR pathway was involved.

Gelatin microsphere coated Fe3O4@graphene quantum dots nanoparticles as a novel magnetic sorbent for ultrasound-assisted dispersive magnetic solid-phase extraction of tricyclic antidepressants in biological samples.

Gelatin microsphere-coated Fe3O4@graphene quantum dots (Fe3O4@GQD@GM) were designed and synthesized as a novel sorbent via ultrasonic-assisted dispersive magnetic solid-phase extraction (UA-DMSPE) method. The synthesized sorbent was identified and confirmed by FT-IR, XRD, VSM, and SEM techniques. UA-DMSPE was combined with corona discharge ion mobility spectrometry for trace determination of desipramine, sertraline, and citalopram. Effective parameters were considered and optimized. The proposed method, under optimal conditions, showed excellent linearity in different concentration ranges (2-700 ng mL-1, R2 > 0.995), repeatability (RSD < 5.1%), good sensitivity (LODs in the range 0.6-1.5 ng mL-1), high preconcentration factor (PF = 207-218), and acceptable relative recoveries (93.5-101.8%). Eventually, this method was used to determine tricyclic antidepressants in various biological samples. Schematic presentation of the microextraction and monitoring of TCAs by ultrasonic-assisted dispersive magnetic solid phase microextraction-ion mobility spectrometry producer.

Glutathione-stabilized Fe3 O4 nanoparticles as the sorbent for magnetic solid-phase extraction of diazepam and sertraline from urine samples through quantitation via high-performance liquid chromatography.

The synthesis and application of glutathione-coated magnetic nanocomposite were introduced with the purpose of developing a stable, cheap, operationally convenient, simple, fast, sensitive, and selective device for the microextraction of diazepam and sertraline for the first time. The prepared glutathione@Fe3 O4 nanocomposite was used as the sorbent in the form of magnetic solid-phase extraction. Afterward, the extracted analytes were desorbed by organic solvent and analyzed by high-performance liquid chromatography-ultraviolet detection. Several influential variables such as desorption time, desorption volume, sample pH, extraction time, and sorbent amount were screened through Plackett-Burman design and then optimized via Box-Behnken design. The obtained results showed that the above-mentioned method enjoys a good linear range (0.2-500 µg/L) with the coefficient of determination higher than 0.9927, low limits of determination (0.07-0.24 µg/L), acceptable limits of quantification (0.22-0.93 µg/L), good enrichment factors (128 and 153), and good spiking recoveries (95-105%) for diazepam and sertraline under the obtained optimized condition. Analyzing the real samples results in the confirmation of the presented method and it can be applied for the analysis of various organic compounds in biological samples.

Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives.

We report a Ni-catalyzed regioselective α-carbonylalkylarylation of vinylarenes with α-halocarbonyl compounds and arylzinc reagents. The reaction works with primary, secondary, and tertiary α-halocarbonyl molecules, and electronically varied arylzinc reagents. The reaction generates γ,γ-diarylcarbonyl derivatives with α-secondary, tertiary, and quaternary carbon centers. The products can be readily converted to aryltetralones, including a precursor to Zoloft, an antidepressant drug.

Stereoselective separation of isomeric sertraline with analytical countercurrent chromatography.

Sertraline is an antidepressant in a group of drugs called selective serotonin reuptake inhibitors. Four stereoisomeric compounds would be produced in its synthetic preparation due to two chiral carbons on its chemical structures. In the present work, stereoselective liquid-liquid extraction of isomeric sertraline with substituted cyclodextrins as stereoselective extractant was investigated. Factors affecting the distribution performance, including organic solvents, types of extractants, pH value, buffer solution of aqueous phase, concentration of extractant and temperature, were investigated. Under optimized conditions, a stereoselectivity of 1.404 was obtained for cis-sertraline and a stereoselectivity of 2.373 was obtained for trans-sertraline when hydroxypropyl-ß-cyclodextrin was used as the stereoselective extractant, and a stereoselectivity of 1.685 was achieved for trans-sertraline with methyl-ß-cyclodextrin as extractant. An unusual stereoselective combination was observed for trans-sertraline and cis-sertraline when sodium carbonate buffer was used. Successful stereoselective separation of trans-sertraline and cis-sertraline, (1S, 4R) and (1R, 4S)-sertraline by analytical countercurrent chromatography with methyl-ß-cyclodextrin as stereoselective selector was achieved, using a biphasic solvent system composed of n-hexane : 0.1 mol L-1 citrate buffer solution with pH7.6 (1:1, v/v).

Determination and photodegradation of sertraline residues in aqueous environment.

Sertraline is an antidepressant drug that has been frequently reported in the aquatic environment and biota. While the research has mostly dealt with its occurrence and toxicity, there is a lack of information pertaining to its environmental transformation. The present study aimed to fill in these gaps by giving an insight into mechanisms of sertraline phototransformation in surface waters, which was recognized as the main transformation pathway for this contaminant. We performed photodegradation experiments in presence of photosensitizers or reaction quenchers to determine rate constants and used them to predict sertraline phototransformation kinetics by "Aqueous Photochemistry of Environmentally occurring Xenobiotics" (APEX) software. It was established that sertraline degrades by pseudo-first order kinetics mostly dominated by direct photolysis, while the presence of certain reactive species including •OH, CO3-• and 3CDOM* further accelerate the compound's breakdown rate. To validate the predicted results, sertraline-spiked surface water was irradiated by sunlight, where the half-life of sertraline at around 1.4 days was estimated. While following the photodegradation kinetics, we also identified five transformation products, of which three were determined in Slovenian surface waters. According to the ECOSAR toxicity prediction, these transformation products will either have comparable or lower toxicity than their parent compound.

Sertraline/ICG-loaded liposome for dual-modality imaging and effective chemo-photothermal combination therapy against metastatic clear cell renal cell carcinoma.

A large number of chemotherapeutic drugs, utilized in the treatment of advanced metastatic clear cell renal cell carcinoma, are typically prone to poor biocompatibility, lack of targeting specificity, and high toxicity, which mostly leads to unsatisfactory clinical outcomes. As a new drug delivery pathway, nanoliposomes have the advantages of simplifying metabolism, reducing drug side-effects, and providing specific targeting, which can potentially improve the therapeutic effect toward tumor therapy. In this study, a clinically integrated nanoliposome containing Sertraline Hydrochloride and indocyanine green (ICG), here named as Ser/ICG@Lip, was successfully synthesized by film-dispersion and hydration-sonication methods. The photoacoustic imaging and near-infrared fluorescence imaging capabilities of this novel nanoliposome were validated in vitro. The high encapsulation rate of Sertraline Hydrochloride and ICG ensured the safety and therapeutic efficacy of the particle. Moreover, our results suggest that chemo-photothermal combination therapy can be more effective than single photothermal or chemotherapy treatments against malignant tumor cells. This is the first study introducing Sertraline Hydrochloride as a liposome-encapsulated chemotherapeutic agent, containing photothermal capabilities, for the treatment of metastatic renal clear cell cancer cells. This novel drug system has potential to evolve into an alternate treatment method for metastatic clear cell renal cell carcinoma.

Sertraline Delivered in Phosphatidylserine Liposomes Is Effective in an Experimental Model of Visceral Leishmaniasis.

Liposomes containing phosphatidylserine (PS) has been used for the delivery of drugs into the intramacrophage milieu. Leishmania (L.) infantum parasites live inside macrophages and cause a fatal and neglected viscerotropic disease, with a toxic treatment. Sertraline was studied as a free formulation (SERT) and also entrapped into phosphatidylserine liposomes (LP-SERT) against intracellular amastigotes and in a murine model of visceral leishmaniasis. LP-SERT showed a potent activity against intracellular amastigotes with an EC50 value of 2.5 µM. The in vivo efficacy of SERT demonstrated a therapeutic failure. However, when entrapped into negatively charged liposomes (-58 mV) of 125 nm, it significantly reduced the parasite burden in the mice liver by 89% at 1 mg/kg, reducing the serum levels of the cytokine IL-6 and upregulating the levels of the chemokine MCP-1. Histopathological studies demonstrated the presence of an inflammatory infiltrate with the development of granulomas in the liver, suggesting the resolution of the infection in the treated group. Delivery studies showed fluorescent-labeled LP-SERT in the liver and spleen of mice even after 48 h of administration. This study demonstrates the efficacy of PS liposomes containing sertraline in experimental VL. Considering the urgent need for VL treatments, the repurposing approach of SERT could be a promising alternative.

An In Vitro Study of Aromatic Stacking of Drug Molecules.

In this paper, drug-drug chemical interactions between two different aromatic compounds were studied by mass spectrometry. Specifically, we examined non-covalent complexes (NCX) between paclitaxel, a chemotherapeutic compound, and medications widely used in palliative care for depression, psychosis, and anxiety. It is unknown whether psychotropic medications directly interact with paclitaxel. Here, we use a simple and rapid electrospray ionization mass spectrometry in vitro assay, which has been predictive in the case of neuropeptides, to measure the relative strength of non-covalent interactions. This chemical interaction is most likely due to the overlap of aromatic rings of π-orbitals between paclitaxel and five commonly used medications: diazepam, clonozepam, sertraline, fluoxetine, and haloperidol. Molecular modeling illustrates that differences in the stability of the NCXs are likely due to the distance between the aromatic rings present in both the paclitaxel and antidepressant medications. Graphical Abstract.

Systematic Development of Sertraline Loaded Solid Lipid Nanoparticle (SLN) by Emulsification-Ultrasonication Method and Pharmacokinetic Study in Sprague-Dawley Rats.

OBJECTIVE: To circumvent the aforementioned problems and for the successful delivery of those newly discovered poorly soluble compounds, researchers have focused on the feasibility of biocompatible lipids such as Solid lipid nanoparticles (SLN) as carrier system. BACKGROUND: Sertraline (SRT) is commercially available as hydrochloride salt. Poor bioavailability (around 44%) of hydrochloride salt is considered to be conversion of salts to free base in the gastrointestinal tract which retard it's absorption. METHODS: Different batches of solid lipid nanoparticles (SLN) were prepared and on the basis of particle size, polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), and drug loading capacity (L) an optimum system was designed. RESULTS: The optimized formulation contains; 5% (w/v) Compritol® E ATO as lipids, 2.5% (w/v) Tween® 80 as surfactant and 0.1% (w/v) SRT as actives. The formulation was freeze-dried using mannitol as a cryoprotectant to control the aggregation of particles during redispersion process. SLN with <110 nm size, <0.2 PDI, >36 mV ZP, >72% EE, and nearly 0.7% L can be formed at appropriate formulation process conditions; homogenization time (HT) and sonication time (ST) at 5 min and 10 min, respectively. XRD studies indicated the presence of amorphous form of drug that is completely encapsulated within the nanoparticulate matrix system. The optimized SLN formulation have shown the highest value of zeta potential (-36.5 mV) confers stability of nanodispersion. Release of drug encapsulated in SLN showed a biphasic pattern and was extended upto 12 hours. The maximum plasma concentration (Cmax) and area under the curve (AUC) in case of sertraline loaded SLN were found 10-fold and 6-fold higher, respectively compared to pure drug. CONCLUSION: The result depicted enhanced extent of absorption of sertraline from SLN compared to plain sertraline. Furthermore, sertraline-loaded SLN were found to be stable at 4°C for 6 months of study period. Hence, the SLN can be used as a potential carrier for successful delivery of poorly water-soluble drugs associated with poor oral bioavailability like sertraline.

Sorption and desorption of selected pharmaceuticals by polyethylene microplastics.

The aim of the present study was to evaluate the sorption and desorption of sulfamethoxazole (SMX), propranolol (PRP) and sertraline (SER) by polyethylene (PE) microplastics in water. After the 96 h mixture, the sorption percentages of pharmaceuticals on PE microplastics decreased according to the following order: SER (28.61%) > PRP (21.61%) > SMX (15.31%). The sorption kinetics were fitted well with the pseudo-second-order model. Both linear and Freundlich models were able to describe the sorption isotherm. The results suggest that the sorption process of the pharmaceuticals may be adequately described by their hydrophobicity and electrostatic interactions. The desorption results showed that 8% and 4% of PRP and SER, respectively, were released from the microplastics within 48 h, but the sorption of SMX was irreversible. The results indicate the potential risks of PRP and SER for bioaccumulation in aquatic organisms via ingestion of the microplastics in aquatic environments.

Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities.

Dysregulation of repressor-element 1 silencing transcription factor REST/NRSF is related to several neuropathies, including medulloblastoma, glioblastoma, Huntington's disease, and neuropathic pain. Inhibitors of the interaction between the N-terminal repressor domain of REST/NRSF and the PAH1 domain of its corepressor mSin3 may ameliorate such neuropathies. In-silico screening based on the complex structure of REST/NRSF and mSin3 PAH1 yielded 52 active compounds, including approved neuropathic drugs. We investigated their binding affinity to PAH1 by NMR, and their inhibitory activity toward medulloblastoma cell growth. Interestingly, three antidepressant and antipsychotic medicines, sertraline, chlorprothixene, and chlorpromazine, were found to strongly bind to PAH1. Multivariate analysis based on NMR chemical shift changes in PAH1 residues induced by ligand binding was used to identify compound characteristics associated with cell growth inhibition. Active compounds showed a new chemo-type for inhibitors of the REST/NRSF-mSin3 interaction, raising the possibility of new therapies for neuropathies caused by dysregulation of REST/NRSF.

Structural basis for recognition of diverse antidepressants by the human serotonin transporter.

Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentrations of neurotransmitters at synapses and in extracellular spaces via blockade of the serotonin transporter. Here we report X-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate-binding site and stabilizing the transporter in an outward-open conformation. These structures explain how residues within the central site orchestrate binding of chemically diverse inhibitors and mediate transporter drug selectivity.

Physicochemical analysis and nonisothermal kinetic study of sertraline-lactose binary mixtures.

In the present study the physicochemical stability of sertraline with lactose was evaluated in drug-excipient binary mixtures. Different physicochemical methods such as differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy, and mass spectrometry were applied to confirm the incompatibility. The final aim of this study was to evaluate the kinetic parameters using a fast and sensitive DSC method. Solid-state kinetic parameters were derived from nonisothermally stressed physical mixtures using different thermal models such as Friedman, Flynn-Wall-Ozawa, and Kissinger-Akahira-Sunose. Overall, the instability of sertraline with lactose was successfully evaluated. Further confirmation was made by tracking the Maillard reaction product of sertraline and lactose by mass spectrometry. DSC scans provided important information about the stability of sertraline in solid-state condition and also revealed the related thermokinetic parameters in order to understand the nature of the chemical instability.