Modeling an Active Peptide Conformation and Designa Competitive Inhibitory Peptide forHMG-CoA Reductase

摘要

The current work presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized se-quence. This approach was performed using the design of a competitive inhibitor for HMG-CoA reductase (HMGR). In a previous design for constrained peptides, a head-to-tail peptide cycle was used as a model of linear analogy in searches for lead peptides with a structure close to an active conformation. Taking into consid-eration the restricted flexibility of linear peptides in the binding site it was pro-posed that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. The eight peptide cycles were selected for a pep-tide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion (V) applied for constrained peptides. Three peptide cycles (FGYVAE, FPYVAE and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC_(50)= 0.4 μM) showed a 1200-fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC_(50)=484 μM) from soybean.