In silico Designing and Optimization of EPO Mimetic Using Combinatorial Library

Erythrpoitin receptor (EPOR) is a cytokine receptor protein, which on activation by binding to erythropoietin (EPO), triggers the intracellular cascade regulating differentiation and proliferation of erythropoietic progenitor cells into mature erythrocytes. EPO is a 34 KD glycoprotein hormone which specifically binds to EPOR and facilitates downstream signalling maintaining an adequate systemic availability of RBCs. For use of blood transfusion in various blood disorders such as anaemia, recombinant EPO and other mimetics have been reported, however, they have been found to be associated with certain risks and less potent to cure diseases. Targeting the binding site of EPOR to design small molecules and peptides which can retain the full agonist activity of the protein EPO may be a promising approach. Using computational approaches, large pool of diverse libraries can be analyzed to bind EPOR efficiently. In this study, the development of small EPO mimetic with therapeutic potential has been explored by using computational approaches. Initially, combinatorial library was designed in two classes, the first class of chemical compounds Lib-C designed by dimer formation of SMND309 by using different linkers and a second class of library Lib-P designed by interaction sites of EPO mimetic human monoclonal antibody ABT007 to EPOR and previously reported mimetic EPO mimetic peptide 1 (EMP1) and ERB1-7. SMND-309 is a novel derivative of salvianolic acid B which activates the EPO receptor, and then stimulates JAK2/STAT3 pathway and regulates erythropoiesis. The screening of combinatorial library resulted in efficient mimetic with the docking Glide score of -7.970 and Energytotal score of -479.7 for chemical compound and peptide respectively, which are comparatively better results to known chemical compound SMND309 and known mimetics EMP1 and ERB1-7. Resulting chemical compound was found to be having a high binding affinity of -41.849 and peptide mimetic was found to stable and hydrophilic in nature.