Mizoribin as a inhibitor for leukocyte immunoglobulin receptor sub family A member3

Abstract

The Leukocyte Immunoglobulin-like Receptors (LILRs) are a family of receptors that was broadly expressed on all leukocytes and have the ability to regulate their function. The increased levels of human LILRA3 in rheumatoid arthritis patients leads to stroke. In quest of designing novel inhibitors against LILRA3 an accurate homology model for the protein was based on crystal structures of 1GOX and 3P2T using Modeller 9V9. The use of multiple templates for structure prediction led us to propose a structure comprising all 439 amino acids of human LILRA3 for the first time. The best model was selected based on GA341 and DOPE score and further assessed through ProSA and PROCHECK. The validated structure was subjected to CASTp analysis ligand binding site determination. N-acetyl-glucosamine (NAG) that has binding affinity towards human LILRA3 was searched for structural analogs from Ligan.Info database. The structural analogs were docked with LILRA3 using Glide v5.7 to propose 17 potential inhibitors with better binding affinity compared to NAG (-7.13 Kcal/mol). Analysis of LILRA3-Lead1 (mizoribin) docking showed best XPGscore of -10.70 Kcal/mol with four hydrogen bonds with Thr425, Glu360, Ser433,Val419. The binding orientations of mizoribin correlated well with NAG binding orientations. Therefore, mizoribin would be encouraging for stroke treatment in rheumatoid arthritis patients.