İnterlökin 1 beta (IL-1ß) için peptid kökenli inhibitör dizaynı

Interleukin 1 beta (IL-1ß) is a pro-inflammatory cytokine which is activated intracellularly by the cleavage of Caspase-1 (Interleukin converting enzyme, ICE). Upon activation, IL-1ß is secreted to the extracellular region. Increased expression of IL-1ß is associated with several diseases such as rheumatoid arthritis and intestinal inflammation. Thus in controlling these kinds of diseases, blocking IL-1ß has great importance. IL-1ß has an embedded receptor (IL-1R) and an accessory protein (IL-1RAcP) in the cell surface. IL-1ß binds to its receptor and to the accessory protein which juxtaposes the intracellular domains of its receptors and causes more expression of IL-1ß. In this study, inhibition of active IL-1ß has been studied extensively by using computational docking tools and techniques. Binding residues of IL-1ß to its receptor were accepted as docking regions. Genetic Algorithm (GA) and Viterbi algorithm (VA) based on the Hidden Markov Model were applied to obtain the most suitable inhibitor candidate by considering its binding free energy and secondary structure conformation. As a result, tripeptide and pentapeptide candidates from Genetic Algorithm and thirty heptapeptide candidates from the Viterbi Algorithm were obtained. Elimination of the candidates was achieved by Molecular Dynamics Simulations by calculating binding free energies of the ligands. Most potent inhibitor for IL-1ß was observed to inhibit IL-1? as well. The unbinding process of ligands was investigated and their probability distribution graphs were examined.