IN SILICO DESIGNING AND OPTIMIZATION OF EPO MIMETICS LIGANDS TARGETING EPOR BINDING

Abstract

EPOR is cytokine receptor protein; activation of cell surface EPOR by EPO triggers the intracellular phosphorylation cascade response for differentiation and proliferation of progenitor cells into RBC. Due to kidney failure EPOR does not activate which cause the anaemia disease arises due to low RBC count. EPO is glycoprotein hormone which stimulates proliferation and final maturation of RBC precursors in bone marrow. For curing anaemia use of recombinant EPO has significantly improved the curing capacity of patients but it is inconvenient and expensive. Finding small molecules and peptides to alternative EPO, is popular in recent years. Therapeutic targeting binding site of EPOR to EPO mimetic antibody, deriving oligopeptide and dimer analogues of chemical compound may be promising approach for designing new small and more efficient mimetic for EPOR activation. Dimerization of compounds reported to increase the efficiency of compound to activate its target protein. In this study combinatorial library designed in two classes, first chemical compounds and second peptides. First class of library designed by SMND309 analogues and dimers. Second class of library by peptide designed from interaction sites of EPO mimetic human monoclonal antibody ABT007 to EPOR and previously reported mimetic EMP1 and ERB1-7. SMND-309 is a novel derivative of salvianolic acid B which activates EPO receptor first, and then stimulate JAK2/STAT3 pathway and regulate erythropoiesis. Through the screening of combinatorial library of series of analogues of chemical compound SMND309 and peptidic mimetics, efficient mimetics are reported with the results of docking and physicochemical properties. Mimetics are found showing good docking results -9.968 and -5.98 of chemical compound and peptide respectively as compared to reported mimetics SMND309, EMP1 and ERB1-7. Resulting Chemical compound evaluated for binding affinity and found with high binding affinity -78.37 and peptide mimetic found stable and hydrophilic in nature.