Lead Design For Classical Autoimmune Reaction Of Neuromyelitis Optica Spectrum Disorders

Objective:Neuromyelitis optica Spectrum Disorders(NMOSD),is an unusual autoimmune demyelinating disease of the central nervous system(CNS).In fact,untreated,this illness may lead to blindness,tetraplegia,and death.Although NMOSD mainly affects the target is the optic nerve and spinal cord,but its effect on cognitive impairment has attracted more and more attention,whether NMO affect the cognitive function of patients,has not yet been finalized.The etiology of NMO remains unclear,a biomarker and possible pathogen of NMO,in the form of the aquaporin 4(AQP4)antibody(NMO-IgG),has recently been identified,and the clinical has no direct target for AQP4 inhibitors.Preventing NMO-IgG binfing would represent a valuable molecular strategy for a focusrd NMOSD therapy.Methods:Investigate cognitive dysfunction in 24-60 year-old neuromyelitis optica(NMO)patients,demographically matched healthy subjects,and MS patients.Outcome measures were cognitive function evaluations,including performance on attention,language,memory,information processing speed,and executive function tests.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 compoundsResults:This analysis indicates that NMO patients aged 24-60 years have significantly worse cognitive performance than demographically matched healthy subjects.However,this was comparable to the performance of demographically matched MS patients.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.Conclusions:The antibody response to AQP4 antigen is an important diagnostic criterion for the NMOSD,but it’s also a key therapeutic target.Based on the analysis of the crystal structure of the receptor,the results show that AQP4 has good drug target characteristics.As a target,the selected compounds are not only suitable for the study of NMOSD,but also for other diseases that are associated with aquaporins.