Computational Drug Design

Computational Design of Novel Peptide Inhibitors of Myostatin

Over the last several years, myostatin inhibition has emerged as a potential strategy for the treatment of cancer cachexia along with other muscle wasting disorders. Myostatin, a member of the TGF-β superfamily, inhibits the process of myogenesis, the development of muscle tissue. First-generation myostatin-directed monoclonal antibodies exhibited poor specificity towards myostatin with respect to other TGF-β ligands, giving rise to many undesired side effects such as the inhibition of wound healing. Rather than focus on antibodies, we have turned our attention towards the protein follistatin, a natural antagonist of myostatin which exists as three alternative splice variants, FS-288, FS-300 and FS-315 with the highest concentration found in the female ovaries followed by the skin. Specifically, we predicted peptides that the action of the proteases, pepsin followed by chymotrypsin on follistatin would give rise to and then modeled the binding of these follistatin-biomi metic peptides with myostatin. The secondary and tertiary structure of myostatin was modeled using the program, PHYRE2