Biological evaluation and molecular modeling of peptidomimetic compounds as inhibitors for O-GlcNAc transferase (OGT).

The vital enzyme O-linked ß-N-acetylglucosamine transferase (OGT) catalyzes the O-GlcNAcylation of intracellular proteins coupling the metabolic status to cellular signaling and transcription pathways. Aberrant levels of O-GlcNAc and OGT have been linked to metabolic diseases as cancer and diabetes. Here, a new series of peptidomimetic OGT inhibitors was identified highlighting the compound LQMed 330, which presented better IC50 compared to the most potent inhibitors found in the literature. Molecular modeling study of selected inhibitors into the OGT binding site provided insight into the behavior by which these compounds interact with the enzyme. The results obtained in this study provided new perspectives on the design and synthesis of highly specific OGT inhibitors.

Molecular dynamic simulations of full-length human purinergic receptor subtype P2X7 bonded to potent inhibitors.

Among the members of purinergic receptors, the family P2X of ionotropic proteins has the ion channel subtype P2X7 that show in studies to be an important molecular target for new drugs. The activity of human P2X7 receptor (hP2X7r) in the body, due to its pro-inflammatory function, can trigger physiological disorders related to chronic inflammatory processes, leading to neural degeneration, neuropathic pain and chronic pain. Recently, two series of promising new inhibitors of the hP2X7r ion channel have been reported. One series consisted of naphthoquinone derivatives and the other composed of triazole derivatives. The main objective of this study was to understand the binding mode differences between the hit compounds of each series and compare them to the native ligand ATP. The hP2X7r ion channel and membrane lipid models were prepared in order to allow study the appropriate protein molecular dynamics. Molecular modeling and molecular dynamics simulation approaches were applied in order to obtain atomistic and molecular details that are involved in intermolecular interactions. Both compounds AN-04 and 9d seem to have affinity to binding in the hP2X7r pore area according to molecular dynamics simulations results. The naphthoquinone derivative AN-04 demonstrated a binding free energy 7.68 fold larger than triazole derivative 9d and 3.8 fold lower than native ligand ATP. These results indicate that compound AN-04 might be a promising lead compound for the development of a novel selective hP2X7r inhibitor.