科研之友
微信
新浪微博
Facebook
分享链接
摘要
Cysteine protease inhibitors are universal regulatory proteins and have recently spawned new interest due to their ability to prevent diseases like carcinogenesis, malaria, autoimmune, and neurodegenerative diseases. However, biologically active natural products that act as protease inhibitors are rare. In the quest of a biologically active natural source of protease inhibitor and interest to find their inhibitory mechanism for drug development, we chose mushrooms as their natural source to ensure acceptability. The present research work aims at discovering motifs in cysteine protease inhibitors which can lead to future development of natural peptide drug candidates. In silico methodologies like structural modeling, protein-protein docking, and structural superimpositions were instrumental to attain the objectives. Cysteine protease inhibitors were found to dock at the active site S1 and S2 pockets of cysteine proteases with amino acid residues 111-125 in clitocypin, 69-76 and 101-115 in macrocypins having the secondary structures of beta-hairpins, were the most important in recognizing target proteases. Peptides derived from the conserved regions of clitocypin and macrocypins were 25 and 18 amino acid residues in length with the primary sequences of Lys-Val-Pro-Ser-Thr-Ala-Asp-Val-Tyr-Ile-Ile-Arg-Ala-Pro-Ile-Gln-Arg-Ile-Gly-Val-Asp-Val-Glu-Val-Gly and Thr-Glu-Phe-Arg-Ile-Asp-Ser-Ile-Pro-Gly-Gln-Trp-Ala-Arg-Ser-Pro-Val-Glu, respectively. They docked with the target proteases showing similar interaction profile as their parent structures. In addition, interaction of peptides with aspartate and serine proteases at sites other than their active site pockets, ensured specificity of their binding to cysteine proteases. Thus, the knowledge derived from this analysis can be utilized for the future development of peptide drugs for cysteine proteases, aiding in modern drug discovery process.
- 出版日期2013-4
