Impact of SNPs, off-targets, and passive permeability on efficacy of BCL6 degrading drugs assigned by virtual screening and 3D-QSAR approach.

B-cell lymphoma 6 (BCL6) regulates various genes and is reported to be overexpressed in lymphomas and other malignancies. Thus, BCL6 inhibition or its tagging for degradation would be an amenable therapeutic approach. A library of 2500 approved drugs was employed to find BCL6 inhibitory molecules via virtual screening. Moreover, the 3D core structure of 170 BCL6 inhibitors was used to build a 3D QSAR model and predict the biological activity. The SNP database was analyzed to study the impact on the destabilization of BCL6/drug interactions. Structural similarity search and molecular docking analyses were used to assess the interaction between possible off-targets and BCL6 inhibitors. The tendency of drugs for passive membrane permeability was also analyzed. Lifitegrast (DB11611) had favorable binding properties and biological activity compared to the BI-3802. Missense SNPs were located at the essential interaction sites of the BCL6. Structural similarity search resulted in five BTB-domain containing off-target proteins. BI-3802 and Lifitegrast had similar chemical behavior and binding properties against off-target candidates. More interestingly, the binding affinity of BI-3802 (against off-targets) was higher than Lifitegrast. Energetically, Lifitegrast was less favorable for passive membrane permeability. The interaction between BCL6 and BI-3802 is more prone to SNP-derived variations. On the other hand, higher nonspecific binding of BI-3802 to off-target proteins could bring about higher undesirable properties. It should also be noted that energetically less desirable passive membrane translocation of Lifitegrast would demand drug delivery vehicles. However, further empirical evaluation of Lifitegrast would unveil its true potential.

Investigate of AQP gene expression in the liver of mice after ischemia-reperfusion.

Ischemia-reperfusion (IR) injury usually occurs during liver transplantation. Aquaporins (AQPs) are transmembrane channels that facilitate water permeability through cell membranes and are essential for the regulation of water homeostasis. Changes in the AQPs expression have been correlated with several inflammatory diseases. Less is known about AQPs expression in hepatic ischemia reperfusion injury. To clarify the roles of AQPs in IR injury, in this current study we examined the gene expression patterns of AQP1, 8 and 9 in the liver after IR injury. Male balb/c mice were exposed to partial (70%) hepatic ischemia for 65 min and then randomized into five groups of reperfusion [0 h (A), 8 h (B), 1 day (C), 3 days (D), and 7 days (E)]. A surgical group was also selected as the sham group. Serum and liver tissue samples were collected for evaluation of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver histopathology. Real time PCR was performed to evaluate the AQPs expression. I/R injury resulted in a significant increase in ALT and AST (p < 0.05) compared to sham mice in each group. The gene expression of AQPs was significantly increased in the IR group compared with the sham group (p < 0.05). AQP8 and AQP1 after 8 h (group B) showed the highest gene expression in comparison with other groups, but the highest level of AQP9 gene expression was observed after 1 day (group C). Pathologic changes in the liver after reperfusion were confirmed the IR. In the IR group cytoplasmic vacuolization, inflammatory cell infiltration and focal necrosis were detected. In conclusion, our findings indicated that the damage caused by ischemia-reperfusion in the liver can change the expression of AQP genes, which can interfere with hepatocellular homeostasis and their function. Upregulation of AQP1, 8 and 9 could contribute to the development of hepatocellular swelling after hepatic IR injury.