Deciphering the Precise Target for Saroglitazar Associated Antiangiogenic Effect: A Computational Synergistic Approach.

Antidiabetic drugs that have a secondary pharmacological effect on angiogenesis inhibition may help diabetic patients delay or avoid comorbidities caused by angiogenesis including malignancies. In recent studies, saroglitazar has exhibited antiangiogenic effects in diabetic retinopathy. The current study investigates the antiangiogenic effects of saroglitazar utilizing the chicken chorioallantoic membrane (CAM) assay and then identifies its precise mode of action on system-level protein networks. To determine the regulatory effect of saroglitazar on the protein-protein interaction network (PIN), 104 target genes were retrieved and tested using an acid server and Swiss target prediction tools. A string-based interactome was created and analyzed using Cytoscape. It was determined that the constructed network was scale-free, making it biologically relevant. Upon topological analysis of the network, 37 targets were screened on the basis of centrality values. Submodularization of the interactome resulted in the formation of four clusters. A total of 20 common targets identified in topological analysis and modular analysis were filtered. A total of 20 targets were compiled and were integrated into the pathway enrichment analysis using ShinyGO. The majority of hub genes were associated with cancer and PI3-AKT signaling pathways. Molecular docking was utilized to reveal the most potent target, which was validated by using molecular dynamic simulations and immunohistochemical staining on the chicken CAM. The comprehensive study offers an alternate research paradigm for the investigation of antiangiogenic effects using CAM assays. This was followed by the identification of the precise off-target use of saroglitazar using system biology and network pharmacology to inhibit angiogenesis.

Deciphering the complexation process of a fluoroquinolone antibiotic, levofloxacin, with bovine serum albumin in the presence of additives.

The current work aims to explore the thermodynamic and conformational aspects for the binding of fluoroquinolone antibacterial drug, levofloxacin (LFC), with bovine serum albumin (BSA) using calorimetric, spectroscopic (UV-visible, fluorescence, circular dichroism, and 1H NMR), dynamic light scattering (DLS) and computational methods (molecular docking). The binding of LFC with BSA at two sequential sites with higher affinity (~103M-1) at the first site has been explored by calorimetry whereas the binding at a single site with affinity of the order of ~104M-1 has been observed from fluorescence spectroscopy. The calorimetric study in the presence of additives along with docking analysis reveals the significant role of electrostatic, hydrogen bonding, and hydrophobic interactions in the association process. The slight conformational changes in protein as well as the changes in the water network structure around the binding cavity of protein have been observed from spectroscopic and DLS measurements. The LFC induced quenching of BSA fluorescence was observed to be initiated mainly through the static quenching process and this suggests the formation of ground state LFC-BSA association complex. The stronger interactions of LFC in the cavity of Sudlow site I (subdomain IIA) of protein have been explored from site marker calorimetric and molecular docking study.