Crystallographic mining driven computer-guided approach to identify the ASK1 inhibitor likely to perturb the catalytic region

The pathological levels of reactive oxygen species (ROS) and oxidative stress has been recognized as a critical driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. ASK1 inhibitors are reported to have the potential to treat clinically important inflammatory pathologies including liver, pulmonary and renal disorders. In view of its biological and pathological significance, inhibition of ASK1 with small molecules has been pursued as an attractive strategy to combat human diseases such as non-alcoholic steatohepatitis (NASH). Despite several ASK1 inhibitors being developed, the failure in Phase 3 clinical trials of most advanced candidate selonsertib’s, underscores to discover therapeutic agents with diverse chemical moiety. Here, by using structural pharmacophore and enumeration strategy on mining co-crystals of ASK1, different scaffolds were generated to enhance the chemical diversity keeping the critical molecular interaction in the catalytic site intact. A total of 15,772 compounds were generated from diverse chemical scaffolds and were evaluated using a virtual screening pipeline. Based on docking and MM-GBSA scores, a lead candidate, S3C-1-D424 was identified from top hits. A comparative molecular dynamics simulations (MD) of APO, Selonsertib and shortlisted potential candidates combined with pharmacokinetics profiling and thermodynamic analysis, demonstrating their suitability as potential ASK1 inhibitors to explore further for establishment towards hit-to-lead campaign. Communicated by Ramaswamy H. Sarma</p

Iodine-Stabilized Cu Nanoparticle Chitosan Composite for Antibacterial Applications

We report herein the synthesis of a new composite consisting of Cu nanoparticles (NPs) and chitosan (CS), which has been found to be stable in the presence of molecular iodine and has also high antimicrobial activities. The composite could be obtained when aqueous CuSO₄ was treated with hydrazine in the presence of CS. The spherical Cu NPs present in the composite were of average diameters 8±4 nm. The NPs were unstable in atmospheric conditions leading to the formation of oxides of Cu. On the other hand, when molecular iodine was added to the medium following synthesis the NPs were rather stable. Studies of antibacterial property were carried out on Gram-negative green fluorescent expressing <i>Escherichia coli</i> bacteria & Gram-positive <i>Bacillus cereus</i> bacteria. The minimum inhibitory concentration (MIC) of the iodinated composite on <i>Escherichia coli</i> was found to be 130.8 μg/mL, which contained 21.5 μg/mL Cu NPs. This determined value of MIC for Cu NPs was much lower than those reported in the literature. Zeta potential (ζ) measurements supported an attractive interaction between iodinated CS-Cu NP composite and bacteria which was further supported by electron microscopic images. Electron microscopic and flow cytometric studies revealed that the iodinated CS-Cu NP composite was attached to the bacterial cell wall, which caused irreversible damage to the membrane, eventually leading to cell death. Mechanism of bactericidal action of the iodinated composite is discussed in light of our findings