title: Peptide design of a competitive inhibitor for HMG-CoA reductase based on statin structure.
abstract: This study investigates a proposed design of a peptide sequence that is based on a bioactive conformation of statins that act as the competitive inhibitors of HMG-CoA for HMGR. To bridge these heterogeneous organic compounds, a conformational aspect relating to an analysis of the flexibility of the peptide molecules and their occupied volumes was applied to the peptide design. The design criterion was formulated in terms of a proximity parameter (Pr), reflecting the probability of an active peptide conformation to approximate the statin. Through a structure-functional analysis of previously synthesized peptides and statin molecules, nine peptides were selected for the peptide library. Comparing the calculated proximity parameters, four peptides (IAVE, YAVE, IVAE, and YVAE) from the library were selected and synthesized. In vitro assays elucidated the inhibition properties for HMGR that are exhibited by these peptides. Among all peptides, YVAE showed the highest ability to inhibit HMGR. A kinetic analysis revealed that this peptide is a competitive inhibitor of HMG-CoA with an equilibrium constant of inhibitor binding (K(i)) of 15.2 +/- 1.4 microM. The calculated coefficient correlation (R) between log (IC(50)) and the inverse value of proximity parameter (1/Pr) was found to be 0.99, indicating a high degree of correlation and efficacy of the given approach in the peptide sequence design.
authors.affiliation: Food Function Research Division, Korea Food Research Institute, Seoul, Korea.
authors.forename: Valeriy V
authors.initials: VV
authors.lastname: Pak
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Minseon
authors.initials: M
authors.lastname: Koo
authors.forename: Nari
authors.initials: N
authors.lastname: Lee
authors.forename: K M
authors.initials: KM
authors.lastname: Shakhidoyatov
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Kwon
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive; D015195:Drug Design; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009842:Oligopeptides; D006903:Hydroxymethylglutaryl CoA Reductases