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This study was supported by the Scientific Research Coordination Unit Istanbul University, Turkey. [BYP-2018-31433, BYP-2018-32798, FYL-2017-26314, ONAP-2423]. TUBITAK (Project numbers: 115S132 and 117S097).

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In silico Analysis of Sulpiride, Synthesis, Characterization and In vitro Studies of its Nanoparticle for the Treatment of Schizophrenia

Publicado en:Current Computer-Aided Drug Design. 16 (2): 104-121 - 2020-01-01 16(2), DOI: 10.2174/1573409915666190627125643

Autores: Kecel-Gunduz, Serda; Budama-Kilinc, Yasemin; Cakir-Koc, Rabia; Zorlu, Tolga; Bicak, Bilge; Kokcu, Yagmur; Kaya, Zeynep; Ozel, Aysen E; Akyuz, Sevim

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Background: Sulpiride, which has selective dopaminergic blocking activity, is a substituted benzamide antipsychotic drug playing a prominent role in the treatment of schizophrenia, which more selective and primarily blocks dopamine D2 and D3 receptor.Objective: This study has two main objectives, firstly; the molecular modeling studies (MD and Docking, ADME) were conducted to define the molecular profile of sulpiride and sulpiride-receptor interactions, another to synthesize polymeric nanoparticles with chitosan, having the advantage of slow/controlled drug release, to improve drug solubility and stability, to enhance utility and reduce toxicity.Methods: Molecular dynamic simulation was carried out to determine the conformational change and stability (in water) of the drug and the binding profile of D3 dopamine receptor was determined by molecular docking calculations. The pharmacological properties of the drug were revealed by ADME analysis. The ionic gelation method was used to prepare sulpiride loaded chitosan nanoparticles (CS NPs). The Dynamic Light Scattering (DLS), UV-vis absorption (UV), Scanning Electron Microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy techniques were carried out to characterize the nanoparticles. In vitro cell cytotoxicity experiments examined with M'n assay on mouse fibroblast (L929), human neuroblastoma (SH-SY5Y) and glioblastoma cells (U-87). The statistical evaluations were produced by ANOVA.Results: The residues (ASP-119, PHE-417) of D3 receptor provided a stable docking with the drug, and the important pharmacological values (blood brain barrier, Caco-2 permeability and human oral absorption) were also determined. The average particle size, PdI and zeta potential value of sulphide-loaded chitosan NPs having a spherical morphology were calculated as 96.93 nm, 0.202 and +7.91 mV. The NPs with 92.8% encapsulation and 28% loading efficiency were found as a slow release profile with 38.49% at the end of the 10 th day. Due to the formation of encapsulation, the prominent shifted wave numbers for C-O, S-O, S-N stretching, S-N-H bending of Sulpiride were also identified. Mitochondria' activity of 1J87, SHSY-5Y and L929 cell line were assayed and evaluated using the SPSS program.Conclusion: To provide more efficient use of Sulpiride having a low bioavailability of the gastrointestinal tract, the nanoparticle formulation with high solubility and bioavailability was designed and synthesized for the first time in this study for the treatment of schizophrenia. In addition to all pharmacological properties of drug, the dopamine blocking activity was also revealed. The toxic effect on different cell lines have also been interpreted.

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