Screening of potent STAT3-SH2 domain inhibitors from JAK/STAT compound library through molecular dynamics simulation.

The Signal Transducer and Activator of Transcription 3 (STAT3) protein is activated consistently in the tumor cells and thus studied as a potent target for cancer prevention. The TYR705-phosphorylated (pTyr) STAT3 forms a homo-dimer by binding to its recognition site in the Src Homology 2 (SH2) domain of another STAT3 monomer, causing cellular survival, proliferation, inflammation, and tumor invasion. Many inhibitors of STAT3-SH2 have recently been identified using both computational and experimental approaches. In this study, we used molecular docking, Absorption, Distribution, Metabolism, and Excretion/Toxicological (ADME/tox) and molecular dynamics modeling to examine binding affinities and specificities of 191 inhibitor drugs from the SELLECKCHEM database. The binding free energies of the inhibitors were calculated by Induced Fit Docking (IFD) prime energy. The binding hotspots of STAT3-SH2 were evaluated via binding energy decomposition and hydrogen bond distribution analysis, and the inhibitor compound's stability was assessed through MD simulation. (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, Picroside I, Saikosaponin D, and Ginsenoside Rk1 were found to be the top hit inhibitor compounds. They exhibited an exceptional docking score, a low binding free energy, interacted with the key amino acid residue, and showed significant ADME/tox moderation. These compounds were further proved to be favorable by their stability in an MD simulation run for 100 ns using GROMACS software. The inhibitors (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, and Saikosaponin D show improved stability in molecular dynamic modeling and are expected to have a significant STAT3-SH2 inhibitory effect against cancer.

Inhibition of mecA and blaCTX-M from MRSA and ESBL strains of diabetic foot infection by screening antibiotics compound library: an in silico analysis.

A computational approach was exploited towards new molecule designing to target the inhibition of resistant genes mecA and blaCTX-M in MRSA and ESBL strains cultured from diabetic foot infected patients. The bioinformatic analysis involves the prediction of protein structures for mecA and blaCTX-M employing the Prime module of Schrodinger. The interactions were examined with the control antibiotics using the modelled protein structures, which revealed that Cefixime and Amikacin showed the highest binding affinity with mecA and blaCTX-M, respectively. According to the predictions of pharmacophores, the ADHRN hypothesis for mecA protein and the ADHR hypothesis for blaCTX-M protein were obtained. Subsequently, the antibiotic compound library from Selleckchem was retrieved, and molecular interactions studies were carried out to explore the interaction profiling of mecA with Tobramycin and blaCTX-M with Acyclovir. Further, the stability of protein-ligand interactions was validated through molecular dynamics simulations. Overall, this study suggests that the predicted pharmacophore model provides in-depth knowledge for repurposing an antibiotic drug with effective inhibition to enhance its therapeutic activity in the currently used ones.Communicated by Ramaswamy H. Sarma.

Pharmacological assessment of Ru(II) complex with GidA protein- A novel topoisomerase II inhibitor towards cancer therapeutics.

The interactions of ruthenium(II) complex with Glucose inhibited division protein A (GidA protein) was studied through various spectroscopic techniques with the ultimate goal of preparing adducts with good selectivity for cancer cells. In all the cases, formation of a tight metal-protein conjugate was observed. The influence of pH, reducing agents and chelators on the formation of adduct was analysed by UV- visible spectroscopy. While there was no effect on the addition of sodium ascorbate, some alterations on some selected bands were seen on the UV-visible spectra on the addition of EDTA. The adduct was stable in the pH range of 5-8. Addition of ruthenium(II) complex effectively quenched the intrinsic fluorescence of GidA and it occurred through static quenching. The effect of ruthenium(II) complex on the conformation of GidA has been examined by analyzing CD spectrum. Though, there was some conformational changes observed in the presence of ruthenium(II) complex, α- helix in the secondary structure of GidA retained its identity. Molecular docking of ruthenium(II) complex with GidA also indicated that GidA docks through hydrophobic interaction. The stable semisynthetic complex (ruthenium(II) complex with GidA) was checked for topoisomerase II inhibition. Relaxation and decatenation assay proved topoisomerase II inhibition of semisynthetic complex.Communicated by Ramaswamy H. Sarma.