In silico drug repositioning of FDA-approved drugs to predict new inhibitors for alpha-synuclein aggregation

One of the hallmarks of Parkinson's disease (PD), a long-term neurodegenerative syndrome, is the accumulation of alpha-synuclein (α-syn) fibrils. Despite numerous studies and efforts, inhibition of α-syn protein aggregation is still a challenge. To overcome this issue, we propose an in silico pharmacophore-based repositioning strategy, to find a pharmaceutical drug that, in addition to their defined role, can be used to prevent aggregation of the α-syn protein. Ligand-based pharmacophore modeling was developed and the best model was selected with validation parameters including 72 % sensitivity, 98 % specificity and goodness score about 0.7. The optimal model has three groups of hydrogen bond donor (HBD), three groups of hydrogen bond acceptor (HBA), and two aromatic rings (AR). The FDA-Approved reports in the ZINC15 database were screened with the pharmacophore model taken from inhibitor compounds. The model identified 22 hits, as promising candidate drugs for Parkinson's therapy. It is noteworthy that among these, 10 drugs have been reported to inhibition of α-syn aggregation or treat/reduce Parkinson's pathogenesis. This model was used to virtual screen ZINC, NCI databases, and natural products from the pomegranate. The results of this screen were filtered for their inability to cross the blood-brain barrier, poor oral bioavailability, etc. Finally, the selected compounds of two ZINC and NCI databases were combined and structurally clustered. Remained compounds were clustered in 28 different clusters, and the 17 compounds were introduced as final candidates

A biophysical study on the mechanism of interactions of DOX or PTX with α-lactalbumin as a delivery carrier

© 2018, The Author(s). Doxorubicin and paclitaxel, two hydrophobic chemotherapeutic agents, are used in cancer therapies. Presence of hydrophobic patches and a flexible fold could probably make α-Lactalbumin a suitable carrier for hydrophobic drugs. In the present study, a variety of thermodynamic, spectroscopic, computational, and cellular techniques were applied to assess α-lactalbumin potential as a carrier for doxorubicin and paclitaxel. According to isothermal titration calorimetry data, the interaction between α-lactalbumin and doxorubicin or paclitaxel is spontaneous and the K (M−1) value for the interaction of α-lactalbumin and paclitaxel is higher than that for doxorubicin. Differential scanning calorimetry and anisotropy results indicated formation of α-lactalbumin complexes with doxorubicin or paclitaxel. Furthermore, molecular docking and dynamic studies revealed that TRPs are not involved in α-Lac’s interaction with Doxorubicin while TRP 60 interacts with paclitaxel. Based on Pace analysis to determine protein thermal stability, doxorubicin and paclitaxel induced higher and lower thermal stability in α-lactalbumin, respectively. Besides, fluorescence lifetime measurements reflected that the interaction between α-lactalbumin with doxorubicin or paclitaxel was of static nature. Therefore, the authors hypothesized that α-lactalbumin could serve as a carrier for doxorubicin and paclitaxel by reducing cytotoxicity and apoptosis which was demonstrated during our in vitro cell studies

Preservative effects of Aspirin on Human Hemoglobin glycation in Diabetic Condition

Abstract Background & aim: Diabetes is a common disease which is characterized by hyperglycemia and the increase of protein glycation. The aim of this study was to investigate the effect of aspirin-induced damage in human hemoglobin in diabetic glycation. Materials & Methods: In this study, hemoglobin extracted from the blood of healthy individuals was incubated in the presence and absence of glucose and aspirin for 5 weeks. The rate of haem glycotation was determined in different conditions by studding products of Heam degradation, sort-band shifting and febrile state. Data were analyzed using One-Way analysis of Variance and Tukey’s test. Results: In the presence of aspirin, the amount of glycation reduced 50%. Furthermore, studies using band-shift sorting and febrile status indicated significant reduce in the amount of protein glycation in the presence of Aspirin. Conclusions: Aspirin reduces extent of glycation when hemoglobin is incubated in the presence of glucose. Likely, aspirin exerts its effect by acetylating amine groups in proteins. Key words: Diabetes, Glycation, Hemoglobin, Aspiri

Role of Copper in the Onset of Alzheimer's Disease Compared to Other Metals

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by amyloid plaques in patients' brain tissue. The plaques are mainly made of beta-amyloid peptides and trace elements including Zn2+, Cu2+, and Fe2+. Some studies have shown that AD can be considered a type of metal dyshomeostasis. Among metal ions involved in plaques, numerous studies have focused on copper ions, which seem to be one of the main cationic elements in plaque formation. The involvement of copper in AD is controversial, as some studies show a copper deficiency in AD, and consequently a need to enhance copper levels, while other data point to copper overload and therefore a need to reduce copper levels. In this paper, the role of copper ions in AD and some contradictory reports are reviewed and discussed