LEAD DESIGN FOR CLASSICAL AUTOIMMUNE REACTION OF NEUROMYELITIS OPTICA SPECTRUM DISORDERS

Neuromyelitis Optica Spectrum Disorders(NMOSD) is a multiple sclerosis-like immunopathology diseases affecting optic nerves and the deposition of a typical immunoglobulin, called NMO-IgG, against the water channel Aquaporin-4(AQP4). Preventing NMO-IgG binding would represent a valuable molecular strategy for a focused NMOSD therapy. In this study, we focused on the designing of AQP4 inhibitors, the dynamic analysis of the key amino acid mutants was carried out by using the method of molecular dynamics(MD), analyzed the crystal structure data of AQP4 on RCSB, the key regions of active centers were studied. Then structure-based design were employed to design novel AQP4 inhibitors using the National Super Computing Platform, have screened more than 350000 compounds The amino acid mutation located in the loop C area did not cause its conformational change, but across the extracellular cyclic structure affected loop A. The mutation of threonine could completely reverse the movement tendency of loop A. The main reason for this phenomenon is that the interaction force between the residues in the loop A and the hydrogen bond between loop A and loop C. Mutation of T137 and P138, although beneficial to the prevention and treatment of NMOSD, but it will affect the choice of permeability. From the screening results, showing many of double-Steroidal Bioconjugates and dense conjugated heterocyclic as lead compounds.